Novel compounds and compositions as cathepsin inhibitors

ABSTRACT

The present invention relates to novel selective cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

This application is based on and claims priority from U.S. ProvisionalApplication Ser. No. 60/257,603 filed on Dec. 22, 2000.

THE INVENTION

This Application relates to compounds and compositions for treatingdiseases associated with cysteine protease activity, particularlydiseases associated with activity of cathepsin S.

DESCRIPTION OF THE FIELD

Cysteine proteases represent a class of peptidases characterized by thepresence of a cysteine residue in the catalytic site of the enzyme.Cysteine proteases are associated with the normal degradation andprocessing of proteins. The aberrant activity of cysteine proteases,e.g., as a result of increase expression or enhanced activation,however, may have pathological consequences. In this regard, certaincysteine proteases are associated with a number of disease states,including arthritis, muscular dystrophy, inflammation, tumor invasion,glomerulonephritis, malaria, periodontal disease, metachromaticleukodystrophy and others. An increase in cathepsin S activitycontributes to the pathology and/or symptomatology of a number ofdiseases. Accordingly, molecules that inhibit the activity of cathepsinS protease are useful as therapeutic agents in the treatment of suchdiseases.

SUMMARY OF THE INVENTION

This Application relates to compounds of Formula I:

X¹ is —C(R¹)(R²)X² or —X³;

X² is cyano, —CHO, —C(R⁷)(R⁸)R⁵, —C(R⁷)(R⁸)CF₃, —C(R⁷)(R⁸)CF₂CF₂R⁹—CH═CHS(O)₂R⁵, —C(R⁷)(R⁸)CF₂C(O)NR⁵R⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)NR⁵R⁶,—C(R⁷)(R⁸)C(R⁷)(R⁸)OR⁵, —C(R⁷)(R⁸)CH₂OR⁵, —C(R⁷)(R⁸)CH₂N(6)SO₂R⁵,—C(R⁷)(R⁸)C(R⁷)(R⁸)N(R⁶)(CH₂)₂OR⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)N(R⁶)(CH₂)₂NR⁶ or—C(R⁷)(R⁸)C(R⁷)(R⁸)R⁵; wherein R⁵ is (C₁₋₄)alkyl,(C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₄₋₁₀)aryl(C₀₋₆)alkyl,(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl or hetero(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl; R⁶is hydrogen or (C₁₋₆)alkyl; R⁷ is hydrogen or (C₁₋₄)alkyl and R⁸ ishydroxy or R⁷ and R⁸ together form oxo; R⁹ is hydrogen, halo,(C₁₋₄)alkyl, (C₅₋₁₀)aryl(C₀₋₆)alkyl or hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl;

X³ represents a group of Formula (a):

in which n is 1 or 2, z is 0 or 1, X⁵ is selected from NR¹⁰, S or O,wherein R¹⁰ is hydrogen or (C₁₋₆)alkyl, and X⁶ is O, S or NR¹¹, whereinR¹¹ is selected from hydrogen, (C₁₋₆)alkyl, —X⁴C(O)OR¹², X⁴C(O)R¹³,—X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴S(O)₂R¹⁵,—X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵ and —X⁴S(O)₂NR¹²R¹⁵, in which X⁴is a bond or (C—)alkylene; R¹² at each occurrence independently ishydrogen or (C₁₋₆)alkyl; R¹³ is hydrogen, (C₁₋₆)alkyl orhalo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl orhalo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl,hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl,hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl orhetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl;

wherein within X¹ any cycloalkyl, heterocycloalkyl, aryl or heteroarylmay be substituted with 1 radical R²⁰ selected from —R¹⁵, —X⁴OR¹⁵,—X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵,—X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹²,—X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and—X⁴NR¹²C(NR¹²)NR¹⁵R¹²; and wherein X¹ and R²⁰ may be substituted furtherwith 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano,halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹²,—X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹²,—X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹²,—X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴ wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are asdefined above;

R¹ and R² are both fluoro; or

R¹ is hydrogen or (C₁₋₆)alkyl and R² is selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, cyano, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹²,—X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³,—X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹²,—X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹²,—X⁴S(O)R¹⁴, —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵,—X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹²,—X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹²,—X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², —X⁴, R¹²,R¹³, R¹⁴ and R¹⁵ are as defined above; or R¹ and R² taken together withthe carbon atom to which both R¹ and R² are attached form(C₃₋₈)cycloalkylene or hetero(C₃₋₈)cycloalkylene; wherein R², saidcycloalkylene and said heterocycloalkylene may be substituted furtherwith 1 to 3 radicals independently selected from (C₁₋₆)alkyl, cyano,halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹²,—X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³,—X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹²,—X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹²,—X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as definedabove;

R³ and R⁴ are independently —C(R¹⁶)(R¹⁷)X⁷, wherein R¹⁶ and R¹⁷ arehydrogen, (C₁₋₆)alkyl or fluoro, or R¹⁶ is hydrogen and R¹⁷ is hydroxyand X⁷ is selected from —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹²,—X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³,—X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹²,—X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴,—X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵,—X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵,—X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵,—X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹², R¹³, R¹⁴and R¹⁵ are as defined above;

wherein within one of R³ or R⁴ any cycloalkyl, heterocycloalkyl, aryl orheteroaryl may be substituted with 1 radical R²¹ selected from —R¹⁵,—X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵,—X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵,—X⁴C(O)NR¹²R¹⁵, —X⁴S(O)₂NR¹⁵R¹², —X⁴ NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹²and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹² and R¹⁵ are as defined above;and wherein each of R³, R⁴ and R²¹ may be substituted further with 1 to5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo,halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹²,—X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³,—X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹²,—X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹²,—X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as definedabove; provided that only one bicyclic ring structure is present withineach of R³ or R⁴; and provided that when X² is cyano and X⁷ within oneof R³ or R⁴ is —X⁴C(O)R¹³ or —X⁴C(O)R¹⁵, wherein X⁴ is a bond, then X⁷within the other of R³ or R⁴ is limited to —X⁴SR¹⁵, —X⁴S(O)R¹⁵ and—X⁴S(O)₂R¹⁵, wherein R¹⁵ is (C₆₋₁₀)aryl(C₁₋₆)alkyl substituted with 1 to5 radicals or hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl optionally substituted with 1to 5 radicals, wherein said radicals are independently selected from(C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro,—X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹²,—X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³,—X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³,—X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴,wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above, provided that theradical is not selected from only halo when R¹⁵ is(C₆₋₁₀)aryl(C₁₋₆)alkyl; and provided that when X² is cyano then X⁷within R³ and R⁴ is not —X⁴C(O)NR¹²R¹², —X⁴C(O)NR¹⁵R¹² or—X⁴C(O)NR¹⁸R¹⁹, wherein X⁴ is a bond and R¹⁸ and R¹⁹ together with thenitrogen atom to which they are attached form hetero(C₃₋₁₀)cycloalkyl orhetero(C₅₋₁₀)aryl;

and the N-oxide derivatives, prodrug derivatives, protected derivatives,individual isomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts and solvates (e.g. hydrates) of suchcompounds and the N-oxide derivatives, prodrug derivatives, protectedderivatives, individual isomers and mixtures of isomers thereof.

A second aspect of the invention is a pharmaceutical composition whichcontains a compound of Formula I or a N-oxide derivative, individualisomer or mixture of isomers thereof, or a pharmaceutically acceptablesalt thereof, in admixture with one or more suitable excipients.

A third aspect of the invention is a method for treating a disease in ananimal in which inhibition of cathepsin S can prevent, inhibit orameliorate the pathology and/or symptomatology of the disease, whichmethod comprises administering to the animal a therapeutically effectiveamount of compound of Formula I or a N-oxide derivative, individualisomer or mixture of isomers thereof; or a pharmaceutically acceptablesalt thereof.

A fourth aspect of the invention is the processes for preparingcompounds of Formula I and the N-oxide derivatives, prodrug derivatives,protected derivatives, individual isomers and mixtures of isomersthereof; and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meanings.

“Alicyclic” means a moiety characterized by arrangement of the carbonatoms in closed non-aromatic ring structures having propertiesresembling those of aliphatics and may be saturated or partiallyunsaturated with two or more double or triple bonds.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of the constituent carbon atoms and may be saturated orpartially unsaturated with two or more double or triple bonds.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having the number of carbon atomsindicated (e.g., (C₁₋₆)alkyl includes methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl,1-propynyl, 2-propynyl, and the like). Alkyl represented along withanother radical (e.g., as in arylalkyl) means a straight or branched,saturated or unsaturated aliphatic divalent radical having the number ofatoms indicated or when no atoms are indicated means a bond (e.g.,(C₆₋₁₀)aryl(C₀₋₃)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl3-phenylpropyl, and the like).

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical having the numberof carbon atoms indicated (e.g., (C₁₋₆)alkylene includes methylene(—CH₂—), ethylene (—CH₂CH₂—), trimethylene (—CH₂CH₂CH₂—), tetramethylene(—CH₂CH₂CH₂CH₂—) 2-butenylene (—CH₂CH═CHCH₂—), 2-methyltetramethylene(—CH₂CH(CH₃)CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like).

“Alkylidene” means a straight or branched saturated or unsaturated,aliphatic, divalent radical having the number of carbon atoms indicated(e.g. (C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH⁻CH═CH₂), and the like).

“Amino” means the radical —NH₂. Unless indicated otherwise, thecompounds of the invention containing amino moieties include protectedderivatives thereof. Suitable protecting groups for amino moietiesinclude acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are Sp² hybridizedand the total number of pi electrons is equal to 4n+2.

“Aryl” means a monocyclic or fused bicyclic ring assembly containing thetotal number of ring carbon atoms indicated, wherein each ring iscomprised of 6 ring carbon atoms and is aromatic or when fused with asecond ring forms an aromatic ring assembly. For example, optionallysubstituted (C₆₋₁₀)aryl as used in this Application includes, but is notlimited to, biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl,2-bromo-5-fluorophenyl, 4-tert-butylphenyl, 4-carbamoylphenyl,4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl,3-chlorocarbonylphenyl, 4-chlorocarbonylphenyl, 2-chloro-4-fluorophenyl,2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl,2,6-dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl,2-ethoxycarbonylphenyl, 2-fluorophenyl, 2-iodophenyl, 4-isopropylphenyl,2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl,naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl,2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl,4-trifluoromethylsulfanylphenyl, and the like.

“Bicycloaryl” means a bicyclic ring assembly containing the number ofring carbon atoms indicated, wherein the rings are linked by a singlebond or fused and at least one of the rings comprising the assembly isaromatic, and any (C₁₋₆)alkylidene, carbocyclic ketone, thioketone oriminoketone derivative thereof (e.g., (C₉₋₁₂)bicycloaryl includesbiphenyl, cyclohexylphenyl, 1,2-dihydronaphthyl,2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl,1,2,3,4-tetrahydronaphthyl, and the like).

“Carbamoyl” means the radical —C(O)NH₂. Unless indicated otherwise, thecompounds of the invention containing carbamoyl moieties includeprotected derivatives thereof. Suitable protecting groups for carbamoylmoieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and thelike and both the unprotected and protected derivatives fall within thescope of the invention.

“Carbocyclic ketone derivative” means a derivative containing the moiety—C(O)—.

“Carboxy” means the radical —C(O)OH. Unless indicated otherwise, thecompounds of the invention containing carboxy moieties include protectedderivatives thereof. Suitable protecting groups for carboxy moietiesinclude benzyl, tert-butyl, and the like.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring carbon atoms indicated, and any (C₁₋₆)alkylidene, carbocyclicketone, thioketone or iminoketone derivative thereof (e.g.,(C₃₋₁₀)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl,adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl,thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like).

“Cycloalkylene” means a divalent saturated or partially unsaturated,monocyclic ring or bridged polycyclic ring assembly containing thenumber of ring carbon atoms indicated, and any carbocyclic ketone,thioketone or iminoketone derivative thereof. For example, the instancewherein “R¹ and R² together with the carbon atom to which both R¹ and R²are attached form (C₃₋₈)cycloalkylene” includes, but is not limited to,the following:

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this Application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g.halo-substituted (C₁₋₃)alkyl includes chloromethyl, dichloromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,2,2,2-trifluoro-1,1-dichloroethyl, and the like).

“Heteroatom moiety” includes —N═, —NR—, —O—, —S— or —S(O)₂—, wherein Ris hydrogen, (C₁₋₆)alkyl or a protecting group.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsindicated, is replaced by heteroatom moiety selected from —N═, —NR—,—O—, —S— or —S(O)₂—, wherein R is hydrogen or (C₁₋₆)alkyl. For example,the instance wherein R¹ and R² together with the carbon atom to whichboth R¹ and R² are attached form hetero(C₃₋₈)cycloalkyl” includes, butis not limited to, the following:

in which R is hydrogen, (C₁₋₆)alkyl, or a protecting group.

“Heteroaryl” as a group or part of a group denotes an optionallysubstituted aromatic monocyclic or multicyclic organic moiety of about 5to about 10 ring members in which one or more of the ring members is/areelement(s) other than carbon, for example nitrogen, NR, oxygen orsulfur, wherein R is hydrogen, (C₁₋₆)alkyl, a protecting group orrepresents the free valence which serves as the point of attachment to aring nitrogen. For example, optionally substituted hetero(C₅₋₁₀)aryl asused in this Application includes, but is not limited to,4-amino-2-hydroxypyrimidin-5-yl, benzothiazol-2-yl,1H-benzoimidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl,4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl,5-carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl,5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydroxypyrimidin-4-yl,fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl,8-hydroxy-5,7-dimethylquinolin-2-yl, 5-hydroxymethylisoxazol-3-yl,3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, 1H-imidazol-2-yl,1H-imidazol-4-yl, 1H-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl,2-methylfur-3-yl, 5-methylfur-2-yl, 1-methyl-1H-imidazol-2-yl,5-methyl-3H-imidazol-4-yl, 5-methylisoxazol-3-yl,5-methyl-2H-pyrazol-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl,5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-yl,2-methylthiazol-4-yl, 5-nitropyrid-2-yl, 2H-pyrazol-3-yl,3H-pyrazol-4-yl, pyridazin-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,5-pyrid-3-yl-2H-[1,2,4]triazol-3-yl, pyrimidin-4-yl, pyrimidin-5-yl,1H-pyrrol-3-yl, quinolin-2-yl, 1H-tetrazol-5-yl, thiazol-2-yl,thiazol-5-yl, thien-2-yl, thien-3-yl, 2H-[1,2,4]triazol-3-yl,3H-[1,2,3]triazol-4-yl, 5-trifluoromethylpyrid-2-yl, and the like.Suitable protecting groups include tert-butoxycarbonyl,benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.Optionally substituted hetero(C₅₋₁₀)aryl as used in this Application todefine R⁵ includes 1H-benzoimidazol-2-yl, pyrimidin-2-yl,benzooxazol-2-yl, benzothiazol-2-yl, pyridazin-3-yl,3-phenyl-[1,2,4]oxadiazol-5-yl, 3-ethyl-[1,2,4]oxadiazol-5-yl, and thelike.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the ring carbon atoms indicated arereplaced by a heteroatom moiety selected from —N═, —NR—, —O— or —S—,wherein R is hydrogen, (C₁₋₆)alkyl, a protecting group or represents thefree valence which serves as the point of attachment to a ring nitrogen,and any carbocyclic ketone, thioketone or iminoketone derivativethereof. For example, optionally substituted hetero(C₈₋₁₀)bicycloaryl asused in this Application includes, but is not limited to,2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like. In general, theterm heterobicycloaryl as used in this Application includes, forexample, benzo[1,3]dioxol-5-yl, 3,4-dihydro-2H-[1,8]naphthyridinyl,3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl,1,2,3,4,5,6-hexahydro[2,2′]bipyridinylyl,3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl, andthe like.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the ring carbon atoms indicated arereplaced by a heteroatom moiety selected from —N═, —NR—, —O— or —S—,wherein R is hydrogen, (C₁₋₆)alkyl, a protecting group or represents thefree valence which serves as the point of attachment to a ring nitrogen,and any carbocyclic ketone, thioketone or iminoketone derivative thereof(e.g., the term hetero(C₅₋₁₀)cycloalkyl includes imidazolidinyl,morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl, and the like. A ketone derivative of piperazinyl would be3-oxo-piperazin-1-yl). Suitable protecting groups includetert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl,2-nitrobenzyl, and the like. Both the unprotected and protectedderivatives fall within the scope of the invention.

“Hydroxy” means the radical —OH. Unless indicated otherwise, thecompounds of the invention containing hydroxy radicals include protectedderivatives thereof. Suitable protecting groups for hydroxy moietiesinclude benzyl and the like.

“Iminoketone derivative” means a derivative containing the moiety—C(NR)—, wherein R is hydrogen or (C₁₋₆)alkyl.

“Isomers” mean compounds of Formula I having identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers”. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”. A compound with one chiral center has two enantiomeric forms ofopposite chirality is termed a “racemic mixture”. A compound that hasmore than one chiral center has 2^(n-1) enantiomeric pairs, where n isthe number of chiral centers. Compounds with more than one chiral centermay exist as ether an individual diastereomers or as a mixture ofdiastereomers, termed a “diastereomeric mixture”. When one chiral centeris present a stereoisomer may be characterized by the absoluteconfiguration of that chiral center. Absolute configuration refers tothe arrangement in space of the substituents attached to the chiralcenter. Enantiomers are characterized by the absolute configuration oftheir chiral centers and described by the R- and S-sequencing rules ofCahn, Ingold and Prelog. Conventions for stereochemical nomenclature,methods for the determination of stereochemistry and the separation ofstereoisomers are well known in the art (e.g., see “Advanced OrganicChemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York,1992). It is understood that the names and illustration used in thisApplication to describe compounds of Formula I are meant to beencompassed all possible stereoisomers. Thus, for example, the nameN-[1-(1-benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramideis meant to includeN—[(S)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramideandN—[(R)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramideand any mixture, racemic or otherwise, thereof.

“Ketone derivative” means a derivative containing the moiety —C(O)—.

“Nitro” means the radical —NO₂.

“Optional” or “optionally” or “may be” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, the phrase “wherein R³,R⁴ and R²¹ may be substituted further by 1 to 5 radicals . . . ” meansthat R³, R⁴ and/or R²¹ may or may not be substituted in order to fallwithin the scope of the invention.

“N-oxide derivatives” means derivatives of compounds of Formula I inwhich nitrogens are in an oxidized state (i.e., O—N) and which possessthe desired pharmacological activity.

“Pathology” of a disease means the essential nature, causes anddevelopment of the disease as well as the structural and functionalchanges that result from the disease processes.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of FormulaI which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or with organic acids such as acetic acid, propionic acid,hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of Formula I. For example anester of a compound of Formula I containing a hydroxy group may beconvertible by hydrolysis in vivo to the parent molecule. Alternativelyan ester of a compound of Formula I containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. Suitableesters of compounds of Formula I containing a hydroxy group, are forexample acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methylsulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. Suitable esters of compounds of Formula I containing a carboxygroup, are for example those described by F. J. Leinweber, Drug Metab.Res., 1987, 18, page 379. An especially useful class of esters ofcompounds of Formula I containing a hydroxy group, may be formed fromacid moieties selected from those described by Bundgaard et al., J. Med.Chem., 1989, 32, page 2503-2507, and include substituted(aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates inwhich the two alkyl groups may be joined together and/or interrupted byan oxygen atom or by an optionally substituted nitrogen atom, e.g. analkylated nitrogen atom, more especially (morpholino-methyl)benzoates,e.g. 3- or 4-(morpholinomethyl)benzoates, and(4-alkylpiperazin-1-yl)benzoates, e.g. 3- or4-(4-alkylpiperazin-1-yl)benzoates.

“Protected derivatives” means derivatives of compounds of Formula I inwhich a reactive site or sites are blocked with protecting groups.Protected derivatives of compounds of Formula I are useful in thepreparation of compounds of Formula I or in themselves may be activecathepsin S inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thioketone derivative” means a derivative containing the moiety —C(S)—.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

Nomenclature:

The compounds of Formula I and the intermediates and starting materialsused in their preparation are named in accordance with IUPAC rules ofnomenclature in which the characteristic groups have decreasing priorityfor citation as the principle group as follows: acids, esters, amides,etc. Alternatively, the compounds are named by AutoNom 4.0 (BeilsteinInformation Systems, Inc.). For example, a compound of Formula I inwhich R¹ is hydrogen, R² is propyl, R³ and R⁴ are eachbenzylsulfonylmethyl; that is, a compound having the followingstructure:

is namedN—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzyl-sulfonylmethyl-propionamide;With reference to formula (I) above, the following are particular andpreferred groupings:X¹ may particularly represent —C(R¹)(R²)X² in which R¹ is hydrogen or(C₁₋₆)alkyl and R² is hydrogen, —X⁴OR¹³ or —R¹⁵, in which within R¹⁵ anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl may be substituted with1 to 3 radicals independently selected from (C₁₋₆)alkyl, cyano, halo,halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹²,—X⁴NR¹²C(O)OR¹², X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴ OR¹³,—X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹²,—X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹²,—X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴ wherein X⁴ is a bond or (C₁₋₆)alkylene, R¹²at each occurrence independently is hydrogen or (C₁₋₆)alkyl, R¹³ ishydrogen, (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkylor halo-substituted(C₁₋₆)alkyl; and X² is cyano, —CHO, —C(O)R⁵,—C(O)CF₃, —C(O)CF₂CF₂R⁹—CH═CHS(O)₂R⁵, —C(O)CF₂C(O)NR⁵R⁶, —C(O)C(O)NR⁵R⁶,—C(O)C(O)OR⁵, —C(O)CH₂OR⁵, —C(O)CH₂N(R⁶)SO₂R⁵, —C(O)C(O)N(R⁶)(CH₂)₂OR⁶,—C(O)C(O)N(R⁶)(CH₂)₂NR⁶ or —C(O)C(O)R⁵; wherein R⁵ is (C₁₋₄)alkyl,(C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₄₋₁₀)aryl(C₀₋₆)alkyl,(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl or hetero(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl, R⁶is hydrogen or (C₁₋₆)alkyl and R⁹ is halo.X¹ may also particularly represent —C(R¹)(R²)X² in which R¹ and R² takentogether with the carbon atom to which both R¹ and R² are attached form(C₃₋₈)cycloalkylene or hetero(C₃₋₈)cycloalkylene, in which thecycloalkylene or the heterocycloalkylene is optionally substituted with1 to 3 radicals independently selected from (C₁₋₆)alkyl and hydroxy andX² is cyano, —CHO, —C(O)R⁵, —C(O)CF₃, —C(O)CF₂CF₂R⁹—CH═CHS(O)₂R⁵,—C(O)CF₂C(O)NR⁵R⁶, —C(O)C(O)NR⁵R⁶, —C(O)C(O)OR⁵, —C(O)CH₂OR⁵,—C(O)CH₂N(R⁶)SO₂R⁵, —C(O)C(O)N(R⁶)(CH₂)₂OR⁶, —C(O)C(O)N(R⁶)(CH₂)₂NR⁶ or—C(O)C(O)R⁵.X¹ may also particularly represent —X³, wherein X³ is a group of formula(b):

in which n is 1 or 2, z is 0 or 1, X⁶ is O or NR¹¹, wherein R¹¹ isselected from hydrogen (C₁₋₆)alkyl, —X⁴C(O)OR¹², —X⁴OC(O)R¹²,—X⁴C(O)R¹³, —X⁴S(O)₂R¹², —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵ and —X⁴C(O)OR¹⁵, inwhich X⁴ is a bond or (C₁₋₆)alkylene; R¹² at each occurrenceindependently is hydrogen or (C₁₋₆)alkyl; R¹³ is hydrogen, (C₁₋₆)alkylor halo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl,hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl,hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl orhetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl; within X³ any cycloalkyl orheterocycloalkyl group may be optionally substituted by substitutedfurther by 1 to 5 radicals independently selected from (C₁₋₆)alkyl,cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹²,—X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹²,—X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³,—X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³,—X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴ and/or1 radical selected from —R¹⁵, —OR¹⁵, —SR¹⁵, —S(O)R¹⁵, —S(O)₂R¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹⁵R¹², —NR¹²C(O)R¹⁵, —NR¹²C(O)OR¹⁵,—C(O)NR¹⁵R¹², —S(O)₂NR¹⁵R¹², —NR¹²S(O)₂R¹⁵, —NR¹²C(O)NR¹⁵R¹² and—NR¹²C(NR¹²)NR¹⁵R¹² wherein X⁴ is a bond or (C₁₋₆)alkylene, R¹² at eachoccurrence independently is hydrogen or (C₁₋₆)alkyl, R¹³ is hydrogen,(C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl orhalo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl,(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl,(C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl,(C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl;R³ and R⁴ may particularly represent —C(R¹⁶)(R¹⁷)X⁷, wherein R¹⁶ and R¹⁷are hydrogen, (C₁₋₆)alkyl or fluoro, or R¹⁶ is hydrogen and R¹⁷ ishydroxy and X⁷ is selected from —X⁴SR¹³, —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹²,—R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵ and —X⁴C(O)NR¹⁵R¹²,wherein X⁴ is a bond or (C₁₋₆)alkylene, R¹² at each occurrenceindependently is hydrogen or (C₁₋₆)alkyl, R¹³ is hydrogen, (C₁₋₆)alkylor halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl orhalo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl,(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl,(C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl,(C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl;

within R³ and R⁴ may be substituted further by 1-5 radicalsindependently selected from (C₁₋₆)alkyl, cyano, halo,halo-substituted(C₁₋₄)alkyl, —X⁴NR¹²C(O)OR¹², —X⁴ OR¹³, —X⁴C(O)OR¹²,—X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴NR¹²S(O)₂R¹³ and —X⁴S(O)₂R¹⁴ and one ofR³ or R⁴ may be further substituted with 1 radical selected from —R¹⁵and —X⁴OR¹⁵, wherein X⁴ is a bond or (C₁₋₆)alkylene, R¹² at eachoccurrence independently is hydrogen or (C₁₋₆)alkyl, R¹³ is hydrogen,(C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl orhalo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl,(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl,(C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl,(C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl.

R³ and R⁴ groups include allylsulfonylmethyl, benzylcarbamoyl-methyl,benzyl, benzylsulfanylmethyl, 2-benzenesulfonyl-ethyl,benzenesulfonylmethyl, 2-benzo[1,3]dioxol-5-yl-2-oxo-ethyl,2-benzo[b]thiophen-2-yl-2-oxo-ethyl, biphenyl-2-ylmethylsulfonylmethyl,biphenyl-4-ylmethyl-sulfonylmethyl, biphenyl-3-ylmethyl,biphenyl-4-ylmethyl, 2-biphenyl-4-yl-2-oxo-ethyl,3,5-bis-trifluoromethyl-benzyl-sulfonylmethyl, 3-bromo-benzyl,2-oxo-2-pyrrolidin-1-yl-ethyl, 2-bromo-benzyl-sulfonylmethyl,(butyl-methyl-carbamoyl)-methyl, 4-tert-butyl-benzylsulfonylmethyl,(3-carbamoyl-phenylcarbamoyl)-methyl,(4-carbamoyl-phenylcarbamoyl)-methyl, 4-carboxy-benzylsulfonylmethyl,2-(3-chloro-benzo[b]thiophen-2-yl)-2-oxo-ethyl,2-(4′-chloro-biphenyl-4-yl)-2-oxo-ethyl,3-chloro-2-fluoro-benzylsulfonylmethyl, 2-chloro-benzylsulfonylmethyl,3-chloro-benzylsulfonylmethyl, 4-chloro-benzylsulfonylmethyl,2-(4-chloro-phenyl)-2-oxo-ethyl,5-chloro-thiophen-2-ylmethylsulfonylmethyl,2-(3-chloro-thiophen-2-yl)-2-oxo-ethyl,2-chloro-5-trifluoromethylbenzylsulfonylmethyl,(cyanomethyl-methyl-carbamoyl)-methyl, cyclohexylcarbamoylmethyl,2-cyclohexyl-ethanesulfonyl, cyclohexylmethylsulfonylmethyl,2-cyclohexyl-ethyl, cyclohexylmethyl, 2-cyano-benzylsulfonylmethyl,cyclopropylmethylsulfonylmethyl, 3-cyano-benzylsulfonylmethyl,4-cyano-benzylsulfonylmethyl, 2,5-dichloro-benzylsulfonylmethyl,2,6-dichloro-benzylsulfonylmethyl, 3,4-dichloro-benzylsulfonylmethyl,2-[2-(1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl,2-[3-(1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl,2-[4-(1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl,2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl,3-(1,1-difluoro-methoxy)-benzylsulfonylmethyl,4-(1,1-difluoro-methoxy)-benzylsulfonylmethyl,2,3-difluoro-benzylsulfonylmethyl, 2,4-difluoro-benzylsulfonylmethyl,2,5-difluoro-benzylsulfonylmethyl, 2,6-difluoro-benzylsulfonylmethyl,3,4-difluoro-benzylsulfonylmethyl, 3,4-dichloro-benzyl-sulfonylmethyl,2-(3,4-difluoro-phenyl)-2-oxo-ethyl,2-(3,4-dimethoxy-phenyl)-2-oxo-ethyl, 4-dimethylcarbamoylmethyl,3,5-dimethyl-isoxazol-4-ylmethylsulfonylmethyl,3,5-dimethyl-benzylsulfonylmethyl,2-(3-fluoro-4-methoxy-phenyl)-2-oxo-ethyl,2-fluoro-3-methyl-benzylsulfonylmethyl, 2-fluoro-benzylsulfonylmethyl,3-fluoro-benzylsulfonylmethyl, 4-fluoro-benzylsulfonylmethyl,2-(4-fluoro-phenyl)-2-oxo-ethyl,4-fluoro-2-trifluoromethoxy-benzyl-sulfonylmethyl,2-fluoro-3-trifluoromethylbenzylsulfonylmethyl,2-fluoro-4-trifluoromethylphenyl-methylsulfonylmethyl,2-fluoro-5-trifluoromethylbenzyl-sulfonylmethyl,2-fluoro-6-trifluoromethyl-benzylsulfonylmethyl,4-fluoro-3-trifluoromethyl-benzylsulfonylmethyl,2-(4-hydroxy-phenyl)-2-oxo-ethyl, isobutylsulfanylmethyl,isopropylcarbamoyl-methyl, 2-(4-methylsulfonylamino-phenyl)-2-oxo-ethyl,2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl, 5-methyl-2-oxo-hexyl,2-methoxy-benzyl-sulfonylmethyl, 4-methoxy-benzylsulfonylmethyl,2-(4-methoxy-phenyl)-2-oxo-ethyl, 3-methyl-benzylsulfonylmethyl,2-methyl-propane-1-sulfonyl, 2-(5-methyl-thiophen-2-yl)-2-oxo-ethyl,2-methyl-thiazol-4-yl-methylsulfonylmethyl5-methyl-thiophene-2-sulfonylmethyl, naphthalen-2-yl,naphthalen-2-ylmethylsulfonylmethyl, 2-naphthalen-2-yl-2-oxo-ethyl,naphthalene-2-sulfonylmethyl, 2-morpholin-4-yl-2-oxo-ethyl,2-oxo-2-piperidin-1-yl-ethyl, 2-oxo-2-(4-phenoxy-phenyl)-ethyl,2-oxo-2-phenyl-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl,2-oxo-2-thiophen-2-yl-ethyl, 2-oxo-2-thiophen-3-yl-ethyl,2-oxo-2-p-tolyl-ethyl, 2-oxo-2-(4-trifluoromethoxy-phenyl)-ethyl,1-oxy-pyridin-2-ylmethylsulfonylmethyl, phenylcarbamoylmethyl,2-benzylsulfonyl-ethyl, benzylsulfonylmethyl, 4-benzylsulfonylmethyl,2-phenylsulfanyl-ethyl, prop-2-ene-1-sulfonylmethyl,pyridin-3-ylcarbamoylmethyl, pyridin-4-ylcarbamoylmethyl,2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl,pyridin-2-ylmethylsulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl,pyridin-4-ylmethylsulfonylmethyl,(5,6,7,8-tetrahydro-naphthalen-1-ylcarbamoyl)-methyl,tetrahydropyran-4-yloxymethyl, thiophene-2-sulfonylmethyl,o-tolylmethylsulfonylmethyl, m-tolylmethylsulfonylmethyl,p-tolylmethylsulfonylmethyl,2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl,2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl,2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl,2-trifluoromethoxy-benzylsulfanylmethyl,2-trifluoromethoxy-benzylsulfonylmethyl,3-trifluoromethoxy-benzylsulfonylmethyl,4-trifluoromethoxy-benzylsulfonylmethyl,2-trifluoromethyl-benzylsulfanylmethyl,2-trifluoromethyl-benzylsulfonylmethyl,3-trifluoromethyl-benzylsulfonylmethyl,4-trifluoromethyl-benzylsulfonylmethyl,2,3,4-trifluoro-benzylsulfonylmethyl,2,3,5-trifluoro-benzylsulfonylmethyl,2,4,5-trifluoro-benzylsulfonylmethyl,2,4,6-trifluoro-benzylsulfonylmethyl and2,5,6-trifluoro-benzylsulfonylmethyl. Preferred R³ and R⁴ groups includeallylsulfonylmethyl, benzylsulfanylmethyl, 3-cyano-benzylsulfonylmethyl,cyclohexylmethyl, 2-difluoromethoxy-benzylsulfonylmethyl,isobutylsulfanylmethyl, (2-methyl-thiazol-4-yl)-methylsulfonylmethyl,2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-piperidin-1-yl-ethyl,2-oxo-2-pyrrolidin-1-yl-ethyl, benzylsulfonylmethyl,tetrahydropyran-4-yloxymethyl, and3-trifluoromethyl-benzylsulfonylmethyl. Particularly preferred R³ and R⁴groups include benzylsulfanylmethyl,2-difluoromethoxy-benzylsulfonylmethyl, 2-morpholin-4-yl-2-oxo-ethyl andbenzylsulfonylmethyl.

It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings referred toherein unless otherwise stated

A particular preferred group of compounds of the invention are compoundsof formula I(a):

wherein R¹, R² and X⁷ are as hereinbefore described, and theircorresponding N-oxides, and their prodrugs, and their protectedderivatives, individual isomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts and solvates (e.g. hydrates) of suchcompounds of formula I(a) and their N-oxides and their prodrugs, andtheir protected derivatives, individual isomers and mixtures of isomersthereof.Compounds of formula I(a) in which R¹ is hydrogen and R² is:

-   -   (i) hydrogen;    -   (ii) —X⁴OR¹³, e.g., —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃;    -   (iii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g., thien-2-yl or        5-methylfuran-2-yl;    -   (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g., phenethyl;    -   (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl]        are preferred.        Compounds of formula I(a) in which R¹ and R² are both methyl are        also preferred.        Compounds of formula I(a) in which R¹ and R² taken together with        the carbon atom to which both R¹ and R² are attached form        (C₃₋₈)cycloalkylene, e.g., cyclopropyl, or        hetero(C₃₋₈)cycloalkylene, e.g., tetrahydropyran-4-yl and        N-methylpiperidin-4-yl, are also preferred.        Compounds of formula I(a) in which X⁷ is:    -   (i) —R¹⁵ or —R¹³, e.g.,    -    or —CH═CH₂, respectively;    -   (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.,    -   (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.,    -   (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.,    -   (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond, R¹³        is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.,        are preferred. Compounds of formula I(a) in which X⁷ represents        are especially preferred.

A preferred group of compounds of the invention are compounds of formulaI(a) in which: R¹ is hydrogen and R² is (i) hydrogen, (ii) X⁴OR¹³, e.g.—CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g.thien-2-yl or 5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g.phenethyl or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; X⁷ is (i)—R¹³ or —R¹⁵, e.g.

or —CH═CH₂, respectively, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bondand R¹⁵ is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.

(iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ ishetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.

(iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or (C₁₋₆)alkylene,R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.

or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond, R¹³ is(C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.

and their corresponding N-oxides, and their prodrugs, and theirprotected derivatives, individual isomers and mixtures of isomersthereof; and the pharmaceutically acceptable salts and solvates (e.g.hydrates) of such compounds and their N-oxides and their prodrugs, andtheir protected derivatives, individual isomers and mixtures of isomersthereof.

A further preferred group of compounds of the invention are compounds offormula I(a) in which: R¹ and R² are both methyl; X⁷ is (i) —R¹⁵, e.g.

or —CH═CH₂, (ii) —X⁴C(O)R^(12a) in which X⁴ is a direct bond and R^(12a)is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.

(iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ ishetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.

(iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or (C₁₋₆)alkylene,R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.

or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond, R¹³ is(C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. —SO₂—CH₂—CH═CH₂,

and their corresponding N-oxides, and their prodrugs, and theirprotected derivatives, individual isomers and mixtures of isomersthereof; and the pharmaceutically acceptable salts and solvates (e.g.hydrates) of such compounds and their N-oxides and their prodrugs, andtheir protected derivatives, individual isomers and mixtures of isomersthereof.A further preferred group of compounds of the invention are compounds offormula I(a) in which: R¹ and R² taken together with the carbon atom towhich both R¹ and R² are attached form (i) (C₃₋₈)cycloalkylene, e.g.cyclopropyl or (ii) hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yland N-methylpiperidin-4-yl; X⁷ is (i) —R¹⁵ or —R¹³, e.g.

or —CH═CH₂, respectively, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bondand R¹⁵ is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.

(iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ ishetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.

(iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or (C₁₋₆)alkylene,R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.

or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond, R¹³ is(C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.

and their corresponding N-oxides, and their prodrugs, and theirprotected derivatives, individual isomers and mixtures of isomersthereof; and the pharmaceutically acceptable salts and solvates (e.g.hydrates) of such compounds and their N-oxides and their prodrugs, andtheir protected derivatives, individual isomers and mixtures of isomersthereof.Another particular group of compounds of the invention are compounds offormula I(b):

wherein R¹, R² and X⁷ are as hereinbefore described, and theircorresponding N-oxides, and their prodrugs, and their protectedderivatives, individual isomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts and solvates (e.g. hydrates) of suchcompounds of formula I(b) and their N-oxides and their prodrugs, andtheir protected derivatives, individual isomers and mixtures of isomersthereof.Compounds of formula I(b) in which R¹ is hydrogen and R² is:

-   -   (vi) hydrogen;    -   (vii) —X⁴OR¹³, e.g. —CH₂—O—CH₃ or —H₂—CH₂—O—CH₃;    -   (viii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl;    -   (ix) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl;    -   (x) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl are preferred.        Compounds of formula I(b) in which R¹ and R² are both methyl are        also preferred.

Compounds of formula I(b) in which R¹ and R² taken together with thecarbon atom to which both R¹ and R² are attached form(C₃₋₈)cycloalkylene, e.g. cyclopropyl or hetero(C₃₋₈)cycloalkylene, e.g.tetrahydropyran-4-yl and N-methylpiperidin-4-yl are also preferred.

Compounds of formula I(b) in which R⁷ and R⁸ together form oxo arepreferred.

Compounds of formula I(b) in which R⁵ is 1H-benzoimidazol-2-yl,pyrimidin-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, pyridazin-3-yl,3-phenyl-[1,2,4]oxadiazol-5-yl, 3-ethyl-[1,2,4]oxadiazol-5-yl arepreferred.

Compounds of formula I(a) in which X⁷ is:

-   -   (vi) —R¹⁵ or —R¹³, e.g.    -   (vii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (viii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (ix) —X⁴SR¹³ or —R¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.    -   (x) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond, R¹³        is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        are preferred. Compounds of formula I(b) in which X⁷ represents        are especially preferred.        A preferred group of compounds of the invention are compounds of        formula I(b) in which: R¹ is hydrogen and R² is (i)        hydrogen, (ii) X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii)        hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl        or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; R⁷ and R⁸        together form oxo; R⁵ is 1H-benzoimidazol-2-yl, pyrimidin-2-yl,        benzooxazol-2-yl, benzothiazol-2-yl, pyridazin-3-yl,        3-phenyl-[1,2,4]oxadiazol-5-yl, 3-ethyl-[1,2,4]oxadiazol-5-yl;        X7 is (i) —R¹⁵, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) (iii) —R⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(b) in which: R¹ and R² are both methyl;        R⁷ and R⁸ together form oxo; R⁵ is 1H-benzoimidazol-2-yl,        pyrimidin-2-yl, benzooxazol-2-yl, benzothiazol-2-yl,        pyridazin-3-yl, 3-phenyl-[1,2,4]oxadiazol-5-yl,        3-ethyl-[1,2,4]oxadiazol-5-yl; X7 is (i) —R^(14a), e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        or —X⁴SR¹⁵ in which X⁴ is a direct bond or (C₁₋₆)alkylene, R¹³        is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(b) in which: R¹ and R² taken together        with the carbon atom to which both R¹ and R² are attached        form (i) (C₃₋₈)cycloalkylene, e.g. cyclopropyl or (ii)        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl; R⁷ and R⁸ together form oxo; R⁵ is        1H-benzoimidazol-2-yl, pyrimidin-2-yl, benzooxazol-2-yl,        benzothiazol-2-yl, pyridazin-3-yl,        3-phenyl-[1,2,4]oxadiazol-5-yl, 3-ethyl-[1,2,4]oxadiazol-5-yl;        X⁷ is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, respectively, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a        direct bond and R¹⁵ is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        in        which X⁴ is a direct bond or (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl        and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Another particular group of compounds of the invention are        compounds of formula I(c):        wherein R¹, R² and X⁷ are as hereinbefore described, and their        corresponding N-oxides, and their prodrugs, and their protected        derivatives, individual isomers and mixtures of isomers thereof;        and the pharmaceutically acceptable salts and solvates (e.g.        hydrates) of such compounds of formula I(c) and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Compounds of formula I(c) in which R¹ is hydrogen and R² is:    -   (xi) hydrogen;    -   (xii) —X⁴OR¹³, e.g. CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃;    -   (xiii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl;    -   (xiv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl;    -   (xv) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl        are preferred.        Compounds of formula I(c) in which R¹ and R² are both methyl are        also preferred.        Compounds of formula I(c) in which R¹ and R² taken together with        the carbon atom to which both R¹ and R² are attached form        (C₃₋₈)cycloalkylene, e.g. cyclopropyl or        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl are also preferred.        Compounds of formula I(c) in which R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl,        e.g. phenyl are preferred.        Compounds of formula I(a) in which X⁷ is:    -   (xi) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, respectively;    -   (xii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xiii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xiv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.    -   (xv) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        —SO₂—CH₂—        are preferred. Compounds of formula I(c) in which X⁷ represents        are especially preferred.        A preferred group of compounds of the invention are compounds of        formula I(c) in which: R¹ is hydrogen and R² is (i)        hydrogen, (ii) X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii)        hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl        or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; R⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenyl; X⁷ is (i) —R¹⁵ or —R¹³,        e.g.        or —CH═CH₂, respectively, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a        direct bond and R¹⁵ is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g. —O—        or —X⁴SR¹⁵ in which X⁴ is a direct bond or (C₁₋₆)alkylene, R¹³        is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(c) in which: R¹ and R² are both methyl;        R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenyl; X⁷ is (i) —R¹⁵ or        —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond, R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹³ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(c) in which: R¹ and R² taken together        with the carbon atom to which both R¹ and R² are attached        form (i) (C₃₋₈)cycloalkylene, e.g. cyclopropyl or (ii)        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl; R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        phenyl; X⁷ is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, respectively, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a        direct bond and R¹⁵ is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Another particular group of compounds of the invention are        compounds of formula I(d):        wherein R¹, R² and X⁷ are as hereinbefore described, and their        corresponding N-oxides, and their prodrugs, and their protected        derivatives, individual isomers and mixtures of isomers thereof;        and the pharmaceutically acceptable salts and solvates (e.g.        hydrates) of such compounds of formula I(d) and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Compounds of formula I(d) in which R¹ is hydrogen and R² is:    -   (xvi) hydrogen;    -   (xvii) —X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃;    -   (xviii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl;    -   (xix) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl;    -   (xx) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl        are preferred.        Compounds of formula I(d) in which R¹ and R² are both methyl are        also preferred.        Compounds of formula I(d) in which R¹ and R² taken together with        the carbon atom to which both R¹ and R² are attached form        (C₃₋₈)cycloalkylene, e.g. cyclopropyl or        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl are also preferred.        Compounds of formula I(d) in which R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl,        e.g. phenyl are preferred.        Compounds of formula I(d) in which R⁶ is hydrogen are preferred.        Compounds of formula I(a) in which X⁷ is:    -   (xvi) —R¹⁵ or —R¹³, e.g.    -   (xvii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xviii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xix) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.    -   (xx) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        are preferred. Compounds of formula I(c) in which X⁷ represents        are especially preferred.        A preferred group of compounds of the invention are compounds of        formula I(d) in which: R¹ is hydrogen and R² is (i)        hydrogen, (ii) X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii)        hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl        or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; R⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenyl; R⁶ is hydrogen; X7 is (i)        —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, respectively, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a        direct bond and R¹⁵ is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkyl, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(d) in which: R¹ and R² are both methyl;        R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenyl; R⁶ is hydrogen; X⁷        is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(d) in which: R¹ and R² taken together        with the carbon atom to which both R¹ and R² are attached        form (i) (C₃₋₈)cycloalkylene, e.g. cyclopropyl or (ii)        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl; R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        phenyl; R⁶ is hydrogen; X⁷ is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Another particular group of compounds of the invention are        compounds of formula I(e):        wherein R¹, R² and X⁷ are as hereinbefore described, and their        corresponding N-oxides, and their prodrugs, and their protected        derivatives, individual isomers and mixtures of isomers thereof;        and the pharmaceutically acceptable salts and solvates (e.g.        hydrates) of such compounds of formula I(e) and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Compounds of formula I(e) in which R¹ is hydrogen and R² is:    -   (xxi) hydrogen;    -   (xxii) —X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃;    -   (xxiii) hetero(C₅—O)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl;    -   (xxiv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl;    -   (xxv) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl        are preferred.        Compounds of formula I(e) in which R¹ and R² are both methyl are        also preferred.        Compounds of formula I(e) in which R¹ and R² taken together with        the carbon atom to which both R¹ and R² are attached form        (C₃₋₈)cycloalkylene, e.g. cyclopropyl or        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl are also preferred.        Compounds of formula I(e) in which R⁵ and R⁶ are (C₁₋₄)alkyl,        e.g. methyl are preferred.        Compounds of formula I(a) in which X⁷ is:    -   (xxi) —R¹⁵ or —R¹³, e.g.    -    or —CH═CH₂, respectively;    -   (xxii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xxiii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xxiv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.    -   (xxv) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        are preferred. Compounds of formula I(e) in which X⁷ represents        are especially preferred.        A preferred group of compounds of the invention are compounds of        formula I(e) in which: R¹ is hydrogen and R² is (i)        hydrogen, (ii) X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii)        hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl        or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; R⁵ is        (C₁₋₄)alkyl, e.g. methyl; X⁷ is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g. —C(O)        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(e) in which: R¹ and R² are both methyl;        R⁵ is (C₁₋₄)alkyl, e.g. methyl; X⁷ is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond        and R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(e) in which: R¹ and R² taken together        with the carbon atom to which both R¹ and R² are attached        form (i) (C₃₋₈)cycloalkylene, e.g. cyclopropyl or (ii)        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl; R⁵ is (C₁₋₄)alkyl, e.g. methyl; X⁷        is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Another particular group of compounds of the invention are        compounds of formula I(f):        wherein R¹, R² and X⁷ are as hereinbefore described, and their        corresponding N-oxides, and their prodrugs, and their protected        derivatives, individual isomers and mixtures of isomers thereof;        and the pharmaceutically acceptable salts and solvates (e.g.        hydrates) of such compounds of formula I(f) and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Compounds of formula I(f) in which R¹ is hydrogen and R² is:    -   (xxvi) hydrogen;    -   (xxvii) —X⁴OR¹³, e.g. —CH₂—O—CH₃ or CH₂—CH₂—O—CH₃;    -   (xxviii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl;    -   (xxix) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl;    -   (xxx) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl are        preferred.        Compounds of formula I(f) in which R¹ and R² are both methyl are        also preferred.        Compounds of formula I(f) in which R¹ and R² taken together with        the carbon atom to which both R¹ and R² are attached form        (C₃₋₈)cycloalkylene, e.g. cyclopropyl or        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl are also preferred.        Compounds of formula I(f) in which R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl,        e.g. benzyl are preferred.        Compounds of formula I(f) in which R⁶ is hydrogen are preferred.        Compounds of formula I(f) in which X⁷ is:    -   (xxvi) —R¹⁵ or —R¹³, e.g.    -    or —CH═CH₂;    -   (xxvii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond, R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xxviii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xxix) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.    -   (xxx) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        are preferred. Compounds of formula I(f) in which X⁷ represents        are especially preferred.        A preferred group of compounds of the invention are compounds of        formula I(f) in which: R¹ is hydrogen and R² is (i)        hydrogen, (ii) X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii)        hetero(C₅₋₁₀)aryl(C₁₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl        or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; R⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. benzyl; R⁶ is hydrogen; X7 is (i)        —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(f) in which: R¹ and R² are both methyl;        R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g. benzyl; R⁶ is hydrogen; X7        is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(f) in which: R¹ and R² taken together        with the carbon atom to which both R¹ and R² are attached        form (i) (C₃₋₈)cycloalkylene, e.g. cyclopropyl or (ii)        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl; R⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        benzyl; R⁶ is hydrogen; X7 is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkyl, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹³ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Another particular group of compounds of the invention are        compounds of formula I(g):        wherein R¹, R² and X7 are as hereinbefore described, and their        corresponding N-oxides, and their prodrugs, and their protected        derivatives, individual isomers and mixtures of isomers thereof;        and the pharmaceutically acceptable salts and solvates (e.g.        hydrates) of such compounds of formula I(g) and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        Compounds of formula I(g) in which R¹ is hydrogen and R² is:    -   (xxxi) hydrogen;    -   (xxxii) —X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃;    -   (xxxiii) hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl;    -   (xxxiv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl;    -   (xxxv) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl        are preferred.        Compounds of formula I(g) in which R¹ and R² are both methyl are        also preferred.        Compounds of formula I(g) in which R¹ and R² taken together with        the carbon atom to which both R¹ and R² are attached form        (C₃₋₈)cycloalkylene, e.g. cyclopropyl or        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl are also preferred.        Compounds of formula I(g) in which X³ is        2-methyl-4-oxo-tetrahydro-furan-3-yl,        2-ethyl-4-oxo-tetrahydro-furan-3-yl,        4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or        (S)-2-Acetoxy-4-oxo-azetidin-3-yl are preferred.        Compounds of formula I(g) in which X7 is:    -   (xxxi) —R¹⁵ or —R¹³, e.g.    -    or —CH═CH₂;    -   (xxxii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xxxiii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.    -   (xxxiv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.    -   (xxxv) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        are preferred. Compounds of formula I(g) in which X7 represents        are especially preferred.        A preferred group of compounds of the invention are compounds of        formula I(g) in which: R¹ is hydrogen and R² is (i)        hydrogen, (ii) X⁴OR¹³, e.g. —CH₂—O—CH₃ or —CH₂—CH₂—O—CH₃, (iii)        hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. thien-2-yl or        5-methylfuran-2-yl, (iv) (C₅₋₁₀)aryl(C₀₋₆)alkyl, e.g. phenethyl        or (v) (C₁₋₆)alkyl, e.g. ethyl, n-propyl or n-butyl; X³ is        2-methyl-4-oxo-tetrahydro-furan-3-yl,        2-ethyl-4-oxo-tetrahydro-furan-3-yl,        4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or        (S)-2-acetoxy-4-oxo-azetidin-3-yl; X7 is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(g) in which: R¹ and R² are both methyl;        X³ is 2-methyl-4-oxo-tetrahydro-furan-3-yl,        2-ethyl-4-oxo-tetrahydro-furan-3-yl,        4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or        (S)-2-acetoxy-4-oxo-azetidin-3-yl; X7 is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond, R¹³ is (C₁₋₆)alkyl        and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.        A further preferred group of compounds of the invention are        compounds of formula I(g) in which: R¹ and R² taken together        with the carbon atom to which both R¹ and R² are attached        form (i) (C₃₋₈)cycloalkylene, e.g. cyclopropyl or (ii)        hetero(C₃₋₈)cycloalkylene, e.g. tetrahydropyran-4-yl and        N-methylpiperidin-4-yl; X³ is        2-methyl-4-oxo-tetrahydro-furan-3-yl,        2-ethyl-4-oxo-tetrahydro-furan-3-yl,        4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or        (S)-2-Acetoxy-4-oxo-azetidin-3-yl; X⁷ is (i) —R¹⁵ or —R¹³, e.g.        or —CH═CH₂, (ii) —X⁴C(O)R¹⁵ in which X⁴ is a direct bond and R¹⁵        is hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iii) —X⁴OR¹⁵ in which X⁴ is a direct bond and R¹⁵ is        hetero(C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, e.g.        (iv) —X⁴SR¹³ or —X⁴SR¹⁵ in which X⁴ is a direct bond or        (C₁₋₆)alkylene, R¹³ is (C₁₋₆)alkyl and R¹⁵ is        (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        or (v) —X⁴S(O)₂R¹³ or —X⁴S(O)₂R¹⁵ in which X⁴ is a direct bond,        R¹³ is (C₁₋₆)alkyl and R¹⁵ is (C₆₋₁₀)aryl(C₀₋₆)alkyl, e.g.        and their corresponding N-oxides, and their prodrugs, and their        protected derivatives, individual isomers and mixtures of        isomers thereof; and the pharmaceutically acceptable salts and        solvates (e.g. hydrates) of such compounds and their N-oxides        and their prodrugs, and their protected derivatives, individual        isomers and mixtures of isomers thereof.

Reference to the preferred embodiments set forth above is meant toinclude all combinations of particular and preferred groups unlessstated otherwise.

Reference to the preferred embodiments set forth above is meant toinclude all combinations of particular and preferred groups.

Particular compounds of the invention are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the carbon atom (C*) of a cyano group, the acylcarbon atom (C*) of one of the fragments (D2-D6 or D8-D56) depicted inTable 4, the vinyl carbon atom (C*) of the fragment (D7) depicted inTable 4 or the acyl carbon atom (C*) of one of the fragments (E1-E14)depicted in Table 5.

Particular compounds of formula I(a) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the carbon atom (C*) of a cyano group depicted inTable 4.

Particular compounds of formula (1b) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the acyl carbon atom (C*) of one of the fragments(D2, D4-D6, D9-D11, D18-D24, D45-D46 or D48-D56) depicted in Table 4.

Particular compounds of formula I(c) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the vinyl carbon atom (C*) of the fragment (D7)depicted in Table 4.

Particular compounds of formula I(d) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the acyl carbon atom (C*) of the fragment (D17)depicted in Table 4.

Particular compounds of formula I(e) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the acyl carbon atom (C*) of the fragment (D15)depicted in Table 4.

Particular compounds of formula I(f) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the acyl carbon atom (C*) of one of the fragments(D8, D25-D44) depicted in Table 4.

Particular compounds of formula I(g) are selected from the compoundsformed by: joining the methylene carbon atom (CH₂*) of one of thefragments (A1 to A116) shown in Table 1 to the carbon atom (*CH*) of oneof the fragments (B1 to B115) shown in Table 2; joining the carbon atom(*CH*) of one of the fragments (B1 to B115) shown in Table 2 to the acylcarbon atom (C*) of one of the fragments (C1 to C13) depicted in Table3; and joining the methylene carbon atom (CH₂*) of fragment D1, thecarbon atom (*CH*) of one of the fragments (C2, C6-C11 or C13) or thetertiary carbon atom (C*) of one of the fragments (C2-C5 or C12)depicted in Table 3 to the acyl carbon atom (C*) of one of the fragments(E1-E14) depicted in Table 5. TABLE 1 A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

A73

A74

A75

A76

A77

A78

A79

A80

A81

A82

A83

A84

A85

A86

A87

A88

A89

A90

A91

A92

A93

A94

A95

A96

A97

A98

A99

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

A111

A112

A113

A114

A115

A116

TABLE 2 B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B52

B53

B54

B55

B56

B57

B58

B59

B60

B61

B62

B63

B64

B65

B66

B67

B68

B69

B70

B71

B72

B73

B74

B75

B76

B77

B78

B79

B80

B81

B82

B83

B84

B85

B86

B87

B88

B89

B90

B91

B92

B93

B94

B95

B96

B97

B98

B99

B100

B101

B102

B103

B104

B105

B106

B107

B108

B109

B110

B111

B112

B113

B114

B115

TABLE 3 C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

TABLE 4 D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

D26

D27

D28

D29

D30

D31

D32

D33

D34

D35

D36

D37

D38

D39

D40

D41

D42

D43

D44

D45

D46

D47

D48

D49

D50

D51

D52

D53

D54

D55

D56

TABLE 5 E1

E2

E3

E4

E5

E6

E7

E8

E9

E10

E11

E12

E13

E14

E15

E16

E17

Particularly preferred compounds of “A”, “B”, “C” and “D” or “A”, “B”and “E” combinations are illustrated in table 6: LENGTHY TABLEREFERENCED HERE US20070049594A1-20070301-T00001 Please refer to the endof the specification for access instructions.

Thus, for example, in table 6 the compound denoted as A2-B4-C6-D8 is theproduct of the combination of group A2 in Table 1 and B4 in Table 2 andC6 in Table 3 and D8 in Table 4, namelyN—[(S)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide:

Particular compounds of the invention are:

-   3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide;-   3-biphenyl-4-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide;-   3-(3-bromo-phenyl)-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide;-   N-cyanomethyl-3-(3-cyano-benzylsulfonyl)-2-benzylsulfonyl-methyl-propionamide;-   N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfanylmethyl]-3-benzylsulfanyl-propionamide;-   N-cyanomethyl-3-(2-trifluoromethyl-benzylsulfanyl)-2-(2-trifluoro-methyl-benzylsulfanylmethyl)-propionamide;-   N-cyanomethyl-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide;-   N-cyanomethyl-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide;-   N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfanylmethyl]-propionamide;-   3-benzylsulfanyl-2-benzylsulfanylmethyl-N-cyanomethyl-propionamide;-   N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide;-   N-cyanomethyl-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide;-   4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N-cyanomethyl-butyramide;-   N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfonyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-propionamide;-   N-cyanomethyl-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide;-   N-cyanomethyl-3-(2-methyl-propane-1-sulfonyl)-2-(2-methyl-propane-1-sulfonylmethyl)-propionamide;-   N-cyanomethyl-3-(2-methyl-thiazol-4-ylmethylsulfonyl)-2-benzyl-sulfonylmethyl-propionamide;-   3-biphenyl-3-yl-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzyl-sulfonylmethyl]-propionamide;-   (3′-{2-(cyanomethyl-carbamoyl)-3-[2-(1,1-difluoro-methoxy)-benzyl-sulfonyl]-propyl}-biphenyl-4-yl)-carbamic    acid ethyl ester;-   N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-(4′-methylsulfonylamino-biphenyl-3-yl)-propionamide;-   3-(3-bromo-phenyl)-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-phenyl-methylsulfonylmethyl]-propionamide;-   N-cyanomethyl-2-((E)-3-phenyl-allyl)-3-benzylsulfonyl-propionamide;-   N-cyanomethyl-3-benzylsulfonyl-2-(3-phenyl-propyl)-propionamide;-   N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide;-   N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide;-   N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-(2-methoxy-benzenesulfonyl)-2-[2-(2-methoxy-benzenesulfonyl)-ethyl]-butyramide;-   4-Benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-butyramide;-   (R)—N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-2-cyclohexylmethyl-3-benzylsulfonyl-propionamide;-   N—[(S)-1-(1-benzothiazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-cyclohexyl-2-cyclohexylmethyl-propionamide;-   N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide;-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide;-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide;-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide;-   N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide;-   4-Morpholin-4-yl-4-oxo-N-[1-(2-oxo-2-phenyl-acetyl)-pentyl]-2-benzylsulfonylmethyl-butyramide;-   N-(1,1-Dimethyl-2-oxazolo[4,5-b]pyridin-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide;-   N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide;-   N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide;-   N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide;-   4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;-   4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-piperidin-1-yl-butyramide;-   4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide;-   4-Morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide;-   N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide;-   4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;-   4-Oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;-   4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide;-   4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-3-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;-   N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide;-   N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide;-   N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;-   2-Cyclohexylmethyl-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide;-   2-Cyclohexylmethyl-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide;-   N-(2-Benzooxazol-2-yl-1-methoxymethyl-2-oxo-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;-   N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyramide;-   2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide;-   2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;-   2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;-   2-(2-Difluoromethoxy-benzylsulfonylmethyl)-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide;-   N-[1-(Benzooxazole-2    carbonyl)-propyl]-2-(2-difluoromethoxy-benzyl-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;-   2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,-   1-(benzooxazole-2-carbonyl)-propyl]-amide;-   (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide;-   2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,-   (S)-1-(5-phenyl-[1,2,4]oxadiazole-3-carbonyl)-propyl]-amide;-   4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide;-   (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide;-   4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-(1,1-Dimethyl-2-oxazol-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-4-Isopropyl-N-1-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-2-benzylsulfonylmethyl-succinamide;-   2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide;-   2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide;-   2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide;-   N-[1-(Benzooxazole-2-carbonyl)-butyl]-2-benzylsulfonyl-3-(tetrahydro-pyran-4-yloxymethyl)-propionamide;-   N-[1-(Benzooxazole-2-carbonyl)-butyl]-3-ethanesulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide;-   N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-cyclopropylmethylsulfonyl-methyl-4-morpholin-4-yl-4-oxo-butyramide;-   2-Cyclopropylmethylsulfonylmethyl-N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide;-   N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;-   2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid    {(S)-1-[(R)-hydroxy-3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-amide;-   2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide;-   2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide;-   2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,-   (S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl}-amide;-   N-[(1S)-1-(Benzooxazol-2-yl-hydroxy-methyl)-3-phenyl-propyl]-2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyramide;-   (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic    acid,-   1-(benzoxazole-2-carbonyl)-propyl]-amide;-   (R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoic    acid, 1-(benzoxazole-2-carbonyl)-propyl]-amide;-   4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-cyclopropyl]-4-oxo-2-benzylsulfonyl    methyl-butyramide;-   N—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide-   N-(3-benzenesulfonyl-1-phenethyl-allyl)-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide;-   N-(3-benzenesulfonylamino-2-oxo-propyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   (S)-2,2-difluoro-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-3-oxo-hexanoic    acid dimethylamide;-   N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide;-   N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   3-Hydroxy-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-azepane-1-carboxylic    acid tert-butyl ester;-   4-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-hydroxy-azepane-1-carboxylic    acid tert-butyl ester;-   3-Hydroxy-4-[2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-azepane-1-carboxylic    acid tert-butyl ester;-   4-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic    acid tert-butyl ester;-   4-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-oxo-azepane-1-carboxylic    acid tert-butyl ester;-   4-[2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-3-oxo-azepane-1-carboxylic    acid tert-butyl ester;-   N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;-   N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;-   3-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-pyrrolidine-1-carboxylic    acid tert-butyl ester;-   4-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic    acid benzyl ester;-   acetic acid    (2S,3S)-3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-4-oxo-azetidin-2-yl    ester; and their corresponding N-oxides, and their prodrugs, and    their protected derivatives, individual isomers and mixtures of    isomers thereof; and the pharmaceutically acceptable salts and    solvates (e.g. hydrates) of such compounds and their N-oxides and    their prodrugs, and their protected derivatives, individual isomers    and mixtures of isomers thereof.    Preferred compounds of the invention are:—-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide    (compound denoted as A64-B4-C11-D6), (Compound 1);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide,    (compound denoted as A69-B32-C11-D6), (Compound 2);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-pentyl]-4-(2-methoxy-benzenesulfonyl)-2-[2-(2-methoxy-benzenesulfonyl)-ethyl]-butyramide,    (compound denoted as A64-B85-C11-D6), (Compound 3);-   4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-butyramide,    (compound denoted as A4-B6-C11-D6), (Compound 4);-   (R)—N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-2-cyclohexylmethyl-3-benzylsulfonyl-propionamide,    (Compound 5);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide,    (compound denoted as A68-B79-C11-D6), (Compound 8);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide,    (compound denoted as A64-B85-C11-D6), (Compound 9);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide,    (compound denoted as A70-B80-C6-D6), (Compound 10);-   N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-4-morpholin-4-yl-4-oxo-butyramide,    (compound denoted as A2-B39-C11-D1), (Compound 25);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide,    (compound denoted as A2-B4-C6-D6), (Compound 29);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide,    (compound denoted as A2-B4-C9-D6), (Compound 30);-   N—[(S)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide,    (compound denoted as A2-B4-C6-D8), (Compound 32);-   N—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide,    (compound denoted as A13-B4-C9-D7), (Compound 38);-   N-(3-Benzenesulfonyl-1-phenethyl-allyl)-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide,    (compound denoted as A13-B4-C10-D7), (Compound 39);-   N-cyanomethyl-3-(3-cyano-benzylsulfonyl)-2-benzylsulfonyl-methyl-propionamide,    (compound denoted as A89-B4-C11-D1), (Compound 40);-   4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide,    (compound denoted as A2-B4-C6-D10), (Compound 41);-   N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide,    (compound denoted as A13-B39-C1-D1), (Compound 48);-   N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfonyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-propionamide,    (compound denoted as A5-B39-C1-D1), (Compound 51);-   N—[(S)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide,    (compound denoted as A13-B4-C6-D8), (Compound 53);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide,    (compound denoted as A13-B39-C11-D6), (Compound 54);-   acetic acid    (2S,3S)-3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-4-oxo-azetidin-2-yl    ester, (compound denoted as A2-B4-E4), (Compound 58);-   N-cyanomethyl-3-(2-methyl-thiazol-4-ylmethylsulfonyl)-2-benzyl-sulfonylmethyl-propionamide,    (compound denoted as A114-B4-C1-D1), (Compound 59);

and the N-oxide derivatives, prodrug derivatives, protected derivatives,individual stereoisomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts and solvates (e.g. hydrates) of suchcompounds and the N-oxide derivatives, prodrug derivatives, protectedderivatives, individual isomers and mixtures of isomers thereof.

Especially preferred compounds of the invention are:—

-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide    (compound denoted as A64-B4-C11-D6), (Compound 1);-   4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-butyramide,    (compound denoted as A4-B6-C11-D6), (Compound 4);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide    (compound denoted as A2-B4-C6-D6), (Compound 29);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide,    (compound denoted as A2-B4-C9-D6), (Compound 30);-   N—[(S)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide,    (compound denoted as A2-B4-C6-D8), (Compound 32);-   N—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide,    (compound denoted as A13-B4-C9-D7), (Compound 38);-   N-(3-Benzenesulfonyl-1-phenethyl-allyl)-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide,    (compound denoted as A13-B4-C10-D7), (Compound 39);-   4-morpholin-4-yl    4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide,    (compound denoted as A2-B4-C6-D10), (Compound 41);-   N—[(S)-1-(1-benzylcarbamoyl-methanoyl)-propyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide,    (compound denoted as A13-B4-C6-D8), (Compound 53);-   N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide,    (compound denoted as A13-B39-C11-D6), (Compound 54);

and the N-oxide derivatives, prodrug derivatives, protected derivatives,individual stereoisomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts and solvates (e.g. hydrates) of suchcompounds and the N-oxide derivatives, prodrug derivatives, protectedderivatives, individual isomers and mixtures of isomers thereof.

Pharmacology and Utility:

The compounds of the invention are selective inhibitors of cathepsin Sand, as such, are useful for treating diseases in which cathepsin Sactivity contributes to the pathology and/or symptomatology of thedisease. For example, the compounds of the invention are useful intreating autoimmune disorders, including, but not limited to, juvenileonset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease,myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritisand Hashimoto's thyroiditis, allergic disorders, including, but notlimited to, asthma, and allogeneic immune responses, including, but notlimited to, organ transplants or tissue grafts.

Cathepsin S also is implicated in disorders involving excessiveelastolysis, such as chronic obstructive pulmonary disease (e.g.,emphysema), bronchiolitis, excessive airway elastolysis in asthma andbronchitis, pneumonities and cardiovascular disease such as plaquerupture and atheroma. Cathepsin S is implicated in fibril formation and,therefore, inhibitors of cathepsins S are of use in treatment ofsystemic amyloidosis.

The cysteine protease inhibitory activities of the compounds of theinvention can be determined by methods known to those of ordinary skillin the art. Suitable in vitro assays for measuring protease activity andthe inhibition thereof by test compounds are known. Typically, the assaymeasures protease-induced hydrolysis of a peptide-based substrate.Details of assays for measuring protease inhibitory activity are setforth in Examples 69, 70, 71 and 72, infra.

Administration and Pharmaceutical Compositions:

In general, compounds of Formula I will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Forexample, therapeutically effective amounts of a compound of Formula Imay range from about 1 micrograms per kilogram body weight (μg/kg) perday to about 1 milligram per kilogram body weight (mg/kg) per day,typically from about 10 μg/kg/day to about 0.1 mg/kg/day. Therefore, atherapeutically effective amount for a 80 kg human patient may rangefrom about 100 μg/day to about 100 mg/day, typically from about 1 μg/dayto about 10 mg/day. In general, one of ordinary skill in the art, actingin reliance upon personal knowledge and the disclosure of thisApplication, will be able to ascertain a therapeutically effectiveamount of a compound of Formula I for treating a given disease.

The compounds of Formula I can be administered as pharmaceuticalcompositions by one of the following routes: oral, systemic (e.g.,transdermal, intranasal or by suppository) or parenteral (e.g.,intramuscular, intravenous or subcutaneous). Compositions can take theform of tablets, pills, capsules, semisolids, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, or any otherappropriate composition and are comprised of, in general, a compound ofFormula I in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the activeingredient. Such excipient may be any solid, liquid, semisolid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, and the like. Liquid and semisolid excipientsmay be selected from water, ethanol, glycerol, propylene glycol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesameoil, and the like). Preferred liquid carriers, particularly forinjectable solutions, include water, saline, aqueous dextrose andglycols.

The amount of a compound of Formula I in the composition may vary widelydepending upon the type of formulation, size of a unit dosage, kind ofexcipients and other factors known to those of skill in the art ofpharmaceutical sciences. In general, a composition of a compound ofFormula I for treating a given disease will comprise from 0.01% w to 10%w, preferably 0.3% w to 1% w, of active ingredient with the remainderbeing the excipient or excipients. Preferably the pharmaceuticalcomposition is administered in a single unit dosage form for continuoustreatment or in a single unit dosage form ad libitum when relief ofsymptoms is specifically required. Representative pharmaceuticalformulations containing a compound of Formula I are described in Example73.

Chemistry:

Processes for Making Compounds of Formula I:

Compounds of the invention may be prepared by the application oradaptation of known methods, by which is meant methods used heretoforeor described in the literature, for example those described by R. C.Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Compounds of Formula I, where X¹ is —NHC(R¹)(R²)X², can be prepared byproceeding as in the following Reaction Scheme 1:

in which each X², R¹, R², R³ and R⁴ are as defined for Formula I in theSummary of the Invention.

Compounds of Formula I can be prepared by condensing an acid of Formula2 with an amino compound of formula NH₂CR¹R²X². The condensationreaction can be effected with an appropriate coupling agent (e.g.,benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP®), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI), O-benzotriazol-1-yl-N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or thelike) and optionally an appropriate catalyst (e.g.,1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt),O-(7-azabenzotrizol-1-yl)-1,1,3,3, tetramethyluroniumhexafluorophosphate(HATU), or the like) and non-nucleophilic base (e.g., triethylamine,N-methylmorpholine, and the like, or any suitable combination thereof)at ambient temperature and requires 5 to 10 hours to complete.

An oxidation step, if required, can be carried out with an oxidizingagent (e.g., Oxone®, metachloroperbenzoic acid or the like) in asuitable solvent (e.g., methanol, water, or the like, or any suitablecombination thereof) at ambient temperature and requires 16 to 24 hoursto complete. Detailed descriptions for the synthesis of a compound ofFormula I by the processes in Reaction Scheme 1 are set forth in theExamples 1 to 6, infra.

Compounds of Formula I, where X¹ is —NHX³, can be prepared by proceedingas in the following Reaction Scheme 2:

in which each X³, R³ and R⁴ are as defined for Formula I in the Summaryof the Invention.

Compounds of Formula I can be prepared by condensing an acid of Formula2 with an amino compound of formula NH₂X³. The condensation reaction canbe effected with an appropriate coupling agent (e.g.,benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP®), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or thelike) and optionally an appropriate catalyst (e.g.,1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt),O-(7-azabenzotrizol-1-yl)-1,1,3,3,tetra-methyluroniumhexafluorophosphate (HATU), or the like) andnon-nucleophilic base (e.g., triethylamine, N-methylmorpholine, and thelike, or any suitable combination thereof) at ambient temperature andrequires 5 to 10 hours to complete.

An oxidation step, if required, can be carried out with an oxidizingagent (e.g., Oxone®, metachloroperbenzoic acid or the like) in asuitable solvent (e.g., methanol, water, or the like, or any suitablecombination thereof) at ambient temperature and requires 16 to 24 hoursto complete.

Compounds of Formula 2 can be prepared by reacting a compound of Formula3 with a compound of Formula R³L:

in which L is a leaving group and R³ and R⁴ are as defined in theSummary of the Invention. The reaction involves coupling (or alkylation)followed by alkaline hydrolysis at a temperature during which thedicarboxylic acid formed undergoes mono-decarboxylation. The couplingreaction can be carried out in the presence of a suitable base (e.g.triethylamine) in a suitable solvent (e.g. ethanol). Thedecarbalkoxylation can be effected under strongly basic conditions (e.g.in the presence of 1N aqueous sodium hydroxide) in a suitable solvent(e.g. ethanol). Detailed descriptions for the synthesis of compounds ofFormula 2 by the process described above are set forth in theReferences, infra

Compounds of Formula 2, in which R³ and R⁴ are benzylsulfonylmethyl, canbe prepared by reacting a compound of Formula 4:

in which R³⁰ is a halo group, with benzyl mercaptan under strongly basicconditions to produce a compound of Formula 5:

followed by reaction with benzyl mercaptan in the presence of a suitablecoupling reagent (e.g. DMAP) and in a suitable solvent (e.g. DMF). Adetailed description of the synthesis of a compound of Formula 2 by asimilar process as that described above is set forth in the References,infra.

Compounds of Formula 2, in which R⁴ is biaryl, can be prepared bycoupling a compound of Formula 6:

in which R³⁰ is a halo group and R³ is as defined in the Summary of theInvention, with a compound of ArL, in which Ar is an aryl group and L isa leaving group, to produce a compound of Formula 2 in which R⁴ isbiaryl. The coupling reaction takes place in the presence of a suitablecatalyst (e.g. tetrakis-triphenylphosphine palladium). A detaileddescription of the synthesis of a compound of Formula 2 by the processdescribed above is set forth in the References, infra.Additional Processes for Preparing Compounds of Formula I:

A compound of Formula I can be prepared as a pharmaceutically acceptableacid addition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid. Alternatively, apharmaceutically acceptable base addition salt of a compound of FormulaI can be prepared by reacting the free acid form of the compound with apharmaceutically acceptable inorganic or organic base. Inorganic andorganic acids and bases suitable for the preparation of thepharmaceutically acceptable salts of compounds of Formula I are setforth in the definitions section of this Application. Alternatively, thesalt forms of the compounds of Formula I can be prepared using salts ofthe starting materials or intermediates.

The free acid or free base forms of the compounds of Formula I can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of Formula I in an acid addition salt formcan be converted to the corresponding free base by treating with asuitable base (e.g., ammonium hydroxide solution, sodium hydroxide, andthe like). A compound of Formula I in a base addition salt form can beconverted to the corresponding free acid by treating with a suitableacid (e.g., hydrochloric acid, etc).

The N-oxides of compounds of Formula I can be prepared by methods knownto those of ordinary skill in the art. For example, N-oxides can beprepared by treating an unoxidized form of the compound of Formula Iwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethyl) at approximately 0° C.Alternatively, the N-oxides of the compounds of Formula I can beprepared from the N-oxide of an appropriate starting material.

Compounds of Formula I in unoxidized form can be prepared from N-oxidesof compounds of Formula I by treating with a reducing agent (e.g.,sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodiumborohydride, phosphorus trichloride, tribromide, or the like) in ansuitable inert organic solvent (e.g., acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of Formula I can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al. (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of Formula I with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of Formula I can be made by meansknown to those of ordinary skill in the art. A detailed description ofthe techniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999. Compounds ofthe present invention may be conveniently prepared, or formed during theprocess of the invention, as solvates (e.g. hydrates). Hydrates ofcompounds of the present invention may be conveniently prepared byrecrystallisation from an aqueous/organic solvent mixture, using organicsolvents such as dioxin, tetrahydrofuran or methanol. Compounds ofFormula I can be prepared as their individual stereoisomers by reactinga racemic mixture of the compound with an optically active resolvingagent to form a pair of diastereoisomeric compounds, separating thediastereomers and recovering the optically pure enantiomer. Whileresolution of enantiomers can be carried out using covalentdiasteromeric derivatives of compounds of Formula I, dissociablecomplexes are preferred (e.g., crystalline diastereoisomeric salts).Diastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and can be readilyseparated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

In summary, the compounds of Formula I are made by a process whichcomprises:

-   (A) reacting a compound of Formula 2:    -   with a compound of the formula NH₂CR¹R²X², in which X², R¹, R²,        R³ and R⁴ are as defined in the Summary of the Invention for        Formula I; or-   (B) reacting a compound of Formula 2 with a compound of the formula    NH₂X³, in which X³, R³ and R⁴ are as defined in the Summary of the    Invention for Formula I; or-   (C) optionally converting a compound of Formula I into a    pharmaceutically acceptable salt;-   (D) optionally converting a salt form of a compound of Formula I to    non-salt form;-   (E) optionally converting an unoxidized form of a compound of    Formula I into a pharmaceutically acceptable N-oxide;-   (F) optionally converting an N-oxide form of a compound of Formula I    its unoxidized form;-   (G) optionally resolving an individual isomer of a compound of    Formula I from a mixture of isomers;-   (H) optionally converting a non-derivatized compound of Formula I    into a pharmaceutically prodrug derivative; and-   (I) optionally converting a prodrug derivative of a compound of    Formula I to its non-derivatized form.

EXAMPLES

The present invention is further exemplified, but not limited by, thefollowing examples that illustrate the preparation of compounds ofFormula I (Examples) and intermediates (References) according to theinvention.

Reference I 3-Benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid

A solution of diethyl bis(hydroxymethyl)malonate (46.95 g, 0.21 moles)(prepared by the method of P. Block, Jr., Organic Synthesis, CollectiveVolume V, 381 (1973)) in methylene chloride (500 mL) was treated withtriethylamine (63 mL) and cooled to −30° C. A mixture of methylsulfonylchloride (35 mL) in methylene chloride (40 mL) was added to the reactionmixture dropwise over 20 minutes and the reaction mixture was allowed tostir at room temperature for 18 hours. The reaction mixture was thenpoured into ice water and the product was extracted with methylenechloride. The organic extracts were washed with saturated aqueous sodiumchloride and then dried over magnesium sulfate. The solvent was removedby rotary evaporation at reduced pressure and the residue wasrecrystallized from t-butylmethyl ether and hexane to give2,2-bis-methylsulfonyloxymethyl-malonic acid diethyl ester (55.04 g).

Sodium (0.268 g, 11.6 mmol) was dissolved in ethanol (25 mL) and theresulting solution was treated with benzyl mercaptan (1.87 mL, 15.9mmol). The reaction mixture was cooled on ice and the2,2-bis-methylsulfonyloxymethyl-malonic acid diethyl ester (2.00 g, 5.31mmol) was added. The reaction mixture was stirred at room temperaturefor 16 hours and then heated at 55° C. for 1.5 hours. The resultingsolution was cooled to room temperature and poured into ice water. Theproduct was extracted with ethyl acetate. The extracts were washed withsaturated aqueous sodium chloride and then dried over magnesium sulfate.The solvent was removed by rotary evaporation at reduced pressure andthe residue was chromatographed on silica gel eluting with ethylacetate/hexane to give 3-benzylsulfanyl-2-benzylsulfanylmethyl-propionicacid ethyl ester (1.589 g, 83% yield).

3-Benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid ethyl ester(1.589 g, 4.41 mmol) in a mixture of potassium hydroxide (1N, 7 mL),water (3 mL), dioxane (30 mL) and ethanol (10 mL) was stirred at roomtemperature for 18 hours. The solvents were removed form the reactionmixture by rotary evaporation at reduced pressure and the residue wasdissolved in water and washed with ether. The aqueous layer was cooledon ice, acidified to pH 2 and the product extracted with ethyl acetate.The extracts were washed with saturated aqueous sodium chloride and thendried over magnesium sulfate. The solvent was removed by rotaryevaporation at reduced pressure to give3-benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid (1.293 g, 88%).

Reference 22-Benzylsulfanylmethyl-3-[2-(1,1-difluoro-methoxy)-benzulsulfanyl]-propionicacid

2-Bromomethylacrylic acid (3.00 g, 18.1 mmol) was dissolved in methanol(100 mL), cooled on an ice bath and treated with benzyl mercaptan.Aqueous sodium hydroxide (1N, 39.8 mL) was added dropwise and thereaction mixture was allowed to adjust to room temperature with stirringfor 23 hours. Methanol was removed by rotary evaporation at reducedpressure and water (100 mL) was added to the residue, which was thenwashed with ether. The aqueous layer was cooled on ice and acidified topH 2.5. The precipitated solid was isolated by filtration and dried togive 2-benzylsulfanylmethyl-acrylic acid (3.346 g, 89%).

A solution of 2-difluoromethoxybenzyl mercaptan (0.534 g, 2.81 mmol),2-benzylsulfanylmethyl-acrylic acid (0.585 g, 2.81 mmol) and4-dimethylaminopyridine (36 mg, 0.3 mmol) in DMF (1.5 ml) was stirred atroom temperature for 20 hours. An additional amount of2-difluoromethoxybenzyl mercaptan (0.201 g) was added to the reactionmixture and stirring was continued for another 24 hours. The reactionmixture was poured into dilute, cold, aqueous HCl and the productextracted with ethyl acetate. The extracts were washed with saturatedaqueous sodium chloride and then dried over magnesium sulfate. Thesolvent was removed by rotary evaporation at reduced pressure and theresidue was chromatographed on silica gel eluting with ethylacetate/hexane to give2-Benzylsulfanylmethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-propionicacid (0.706 g).

Reference 3 2-Benzylsulfanylmethyl-3-cyclohexyl-propionic acid

A solution of diethyl-2-cyclohexylmethyl malonate (2.56 g), 37% aqueousformaldehyde (0.80 mL), potassium bicarbonate (0.08 g) and ethanol (2.5mL) was stirred at room temperature for 20 hours. Saturated aqueousammonium sulfate (10 mL) was added to the reaction and the productextracted with ethyl acetate. The extracts were washed with saturatedaqueous sodium chloride and then dried over magnesium sulfate. Thesolvent was removed by rotary evaporation at reduced pressure and theresidue was chromatographed on silica gel eluting with ethylacetate/hexane to give 2-cyclohexylmethyl-2-hydroxymethyl-malonic aciddiethyl ester (1.31 g).

A solution of 2-cyclohexylmethyl-2-hydroxymethyl-malonic acid diethylester (1.31 g, 4.13 mmol) in methylene chloride (20 mL) and triethylamine (1.16 mL, 8.00 mmol) was cooled to −40° C. A solution ofmethylsulfonyl chloride (0.402 mL, 5.2 mmol) in methylene chloride (4mL) was added to the reaction mixture over 5 minutes. The reactionmixture was warmed to −10° C. over 1 hour and then poured into colddilute aqueous HCl. The product was extracted with ethyl acetate, theextracts were washed with saturated aqueous sodium chloride and thendried over magnesium sulfate. The solvent was removed by rotaryevaporation at reduced pressure to give2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester(1.505 g).

Sodium (0.097 g, 4.2 mmol) was dissolved in ethanol (10 mL) and theresulting solution was cooled to 0° C. and treated with a mixturecomprising benzyl mercaptan (0.493 mL, 4.2 mmol) and2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester(1.466 g, 4.02 mmol). The reaction was stirred at room temperature for17 hours, 53° C. for 20 hours and 73° C. for 24 hours. The ethanol wasremoved by rotary evaporation, the reaction mixture was poured intowater and the product was extracted with ethyl acetate. The extractswere washed with saturated aqueous sodium chloride and then dried overmagnesium sulfate. The solvent was removed by rotary evaporation atreduced pressure and the residue was chromatographed on silica geleluting with ethyl acetate/hexane to give2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid ethyl ester (0.237g).

A mixture of 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid ethylester (0.230 g), dioxane (10 mL), sodium hydroxide (1N, 3 mL), water (2mL) and ethanol (4 mL) was stirred for 20 hours at room temperature. Thesolvents were evaporated and the residue dissolved in water (50 mL). Theaqueous solution was washed twice with ether and then acidified to pH2.The product was extracted from the aqueous solution with ethyl acetateand the extracts were washed with saturated aqueous sodium chloride andthen dried over magnesium sulfate. The solvent was removed by rotaryevaporation at reduced pressure to give acid2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid (0.210 g).

Reference 4 4-Benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-butyric acid

A mixture of 2-iodoethylphenyl sulfide (19.81 g, 75 mmol), diethylmalonate (4.80 g, 30 mmol), potassium carbonate (10.35 g, 75 mmol) andDMF (40 mL) was heated at 52° C. for 18 hours. More potassium carbonate(10 g) was added and the reaction was continued at 52° C. for another 8hours. The reaction mixture was cooled, diluted with ice water and theproduct extracted with ethyl acetate. The extracts were washed withsaturated aqueous sodium chloride and then dried over magnesium sulfate.The solvent was removed by rotary evaporation at reduced pressure andthe residue was chromatographed on silica gel eluting with ethylacetate/hexane to give 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic aciddiethyl ester (5.648 g).

A solution of 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid diethylester (5.614 g) in ethanol (100 mL) was treated with lithium hydroxide(2.84 g) in water (10 mL). The reaction mixture was heated at 49° C. for17 hours followed by 85° C. for 2 hours. The solvents were evaporated atreduced pressure to give a residue that was treated with water (100 mL)and washed with ether. The aqueous layer was cooled on ice, acidifiedand the product extracted with ethyl acetate. The extracts were driedover magnesium sulfate. The solvent was removed by rotary evaporation atreduced pressure to give acid 2,2-bis-(2-phenylsulfanyl-ethyl)-malonicacid (5.628 g).

2,2-Bis-(2-phenylsulfanyl-ethyl)-malonic acid (5.628 g) was heated at150° C. for 30 minutes. The reaction mixture was cooled to roomtemperature, dissolved in ethyl acetate and washed with aqueous sodiumbicarbonate. The ethyl acetate solution was washed with saturatedaqueous sodium chloride and then dried over magnesium sulfate. Thesolvent was removed by rotary evaporation at reduced pressure and theresidue was chromatographed on silica gel eluting with ethylacetate/hexane to give4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyric acid (1.831 g).

A solution of 4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyric acid(0.332 g) in methanol (10 mL) was treated with a solution of Oxone®(1.87 g in 10 mL of water). After stirring 18 hours at room temperaturethe reaction mixture was diluted with water (30 mL) and evaporated underreduced pressure to remove the methanol. The product was extracted withethyl acetate. The extracts were washed with saturated aqueous sodiumchloride and then dried over magnesium sulfate. The solvent was removedby rotary evaporation and the resulting oil was crystallized fromt-butylmethyl ether to give4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-butyric acid (0.315 g).

Reference 54-Morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyricacid

A solution of 3-methylene-dihydro-furan-2,5-dione (5.9 g, 52.7 mmol) inCH₂Cl₂ (200 mL) was cooled to 0° C. before adding morpholine (4.6 mL,52.7 mmol) slowly over 5 minutes. The ice bath was removed and themixture was stirred at room temperature for 1 hour. The solvent wasevaporated under vacuum to 2-Methylene-4-morpholin-4-yl-4-oxo-butyricacid.

A mixture of 2-methylene-4-morpholin-4-yl-4-oxo-butyric acid (2 g, 10.03mmol), in DMF (5 mL), 2-trifluoromethylbenzyl mercaptan (1.93 g, 10.03mmol) and DMAP (122 mg, 1.0 mmol) was stirred at ambient temperature for16 hours. Methanol (200 mL) and a saturated aqueous solution of Oxone®(20 g, 32.5 mmol) were added with continued stirring for 2 hours.Methanol was removed under vacuum and the aqueous residue was dilutedwith 200 mL of water. The crystallized product was filtered, washed withwater, and dried under vacuum to yield4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyricacid (0.95 g) as a white solid.

Compounds of Formula I in which R³ is —CH₂SR¹⁴ (R¹⁴ is as described inthe summary of the invention) can be synthesized by the followingreaction protocol:

Compound 1 was prepared as S or R enantiomers using the method describedby Crawforth et al. J. Chem. Soc., Perkin Trans. 1, 1721-1725, 1998.

Compound 2 was prepared by dissolving compound 1 in methylene chloridewith triphenylphosphine (1.1 equivalents) followed by the slow additionof N-bromosuccinamide (1.05 equivalents) over a 5 minute period and thereaction was allowed to stir for 3-8 hours at room temperature. Themixture was then extracted with water and brine, then dried over sodiumsulfate. After concentrating the residue was dissolved in ether and asmall amount of heptane was added to remove unwanted solids. Afterfiltering and concentration the resulting bromide was used withoutfurther purification. This intermediate was dissolved in THF thenpotassium thioacetate (1.1 equivalents) was added in one portion and thereaction was stirred for 3 to 24 hours at room temperature. The solventwas removed and the residue taken up in ethanol. Sodium hydroxide wasadded (2.2 equivalents) and the reaction was stirred for 10 to 60minutes at room temperature. 1 equivalent of a halo-substituted compound(e.g. benzyl bromide, isobutyl bromide, cyclopropylmethyl bromide; seeother elements from table 2, supra) was added with stirring for 6 to 24hours at room temperature. The ethanol was removed under vacuum and themixture was diluted with water and made acidic with 4 N HCl (pH=1 to 2).The aqueous layer was extracted with ethyl acetate 3 times and theorganic layer was dried over sodium sulfate and concentrated. Theproduct was purified on silica gel using a mixture of ethyl acetate andheptane (gradient 1:4 to 4:1) to give compound 2.

Compound 3 was made by stirring a solution of compound 2 in THF withmorpholine (2 equivalents), which was heated, to reflux for 1 to 24hours. Concentration of the mixture and redissolving in methylenechloride and extraction with diluted HCl removed the excess morpholine.The organic layer was washed with saturated sodium bicarbonate, driedover sodium sulfate and concentrated to dryness. The product waspurified on silica gel using a mixture of ethyl acetate and heptane(gradient 1:4 to 4:1) to give compound 3.

Compound 4 was prepared from compound 3 by dissolving in a 1:1 mixtureof methanol/water and adding oxone® (approximately 1 equivalent) over aperiod of 1 to 3 hours until a positive starch-iodine test wasmaintained. The solvent was removed under vacuum and the residuedissolved in a 1:1:1 mixture of water/acetonitrile/carbon tetrachloride.This was followed by the addition of sodium periodate and ruthenium(III) chloride which was vigorously stirred for 6 to 24 hours at atemperature below 40° C. The reaction was filtered through celite andconcentrated to remove acetonitrile and carbon tetrachloride. Theaqueous layer was extracted with ethyl acetate 3 times and the organiclayer dried over sodium sulfate and concentrated. The product waspurified on silica gel using a mixture of ethyl acetate and heptane (1:4to 4:1) to ethyl acetate and methanol (19:1 to 4:1) to give compound 4,which was obtained as R or S enantiomers.

Reference 6 (S)-4-Amino-2,2-difluoro-3-hydroxy-hexanoic aciddimethylamide

Activated zinc dust (2.16 g, 33 mmol) was suspended in dry THF (2 mL). Amixture of ethyl bromodifluoro acetate (6.5 g, 32 mmol) and(1S)-(1-formyl-propyl) carbamic acid tert-butyl ester (2 g, 10.7 mmol),in THF (10 mL), was added over 20 minutes while the mixture wassonicated. After complete addition, sonication was continued for afurther 30 minutes. The mixture was then diluted with ethyl acetate (200mL) and washed with 1N aqueous KHSO₄, brine, dried with magnesiumsulfate and evaporated. The crude product was dissolved in ethanol (15mL) and a solution of dimethylamine (40% in water; 2 mL) was added.After stirring for 16 hours at ambient temperature, the solvents wereevaporated and the product was purified by flash chromatography onsilica gel (hexane/ethyl acetate ratio of 3:1) to yield 200 mg ofcolorless oil.

The amide was dissolved in a mixture of TFA/dichloromethyl (1:1; 6 mL),stirred for 1 hour and evaporated to dryness. The product,(4S)-4-amino-2,2-difluoro-3-hydroxy-hexanoic acid dimethylamide, wasobtained as the TFA salt and used without further purification.

Reference 7 (S)-3-Amino-2-hydroxy-pentanoic acid benzylamide

(1S)-(2-Cyano-1-ethyl-2-hydroxyethyl)carbamic acid tert-butyl ester (10g, 46.7 mmol) was dissolved in 1,4-dioxane (100 mL). Anisole (5 mL) wasadded and then concentrated HCl (100 mL). The mixture was heated underreflux for 24 hours. The mixture was evaporated to dryness under vacuumand re-dissolved in 100 mL water. The solution was washed with ether andthen neutralized with saturated aqueous NaHCO₃. Di-tert-butyldicarbonate (10 g, 46 mmol) was added with 1,4-dioxane (200 mL), and themixture was stirred at ambient temperature for 24 hours. The dioxane wasremoved under vacuum and the remaining aqueous solution was washed withether. The solution was acidified with 1N HCl and extracted with ethylacetate. The combined organic layers were washed with brine, dried withmagnesium sulfate and evaporated to yield3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (4.5 g) as yellowishoil.

3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.29 mmol)was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). Asolution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) indichloromethyl (4 mL) was added in one portion. The mixture was stirredat ambient temperature for 2 hours. After dilution with ethyl acetate(150 mL), the solution was washed with 1N aqueous HCl, water, saturatedaqueous NaHCO₃ solution and brine. The resultant mixture was dried withmagnesium sulfate and evaporated under vacuum to yield(S)-3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a whitesolid.

(S)-3-Amino-2-hydroxy-pentanoic acid benzylamide was dissolved in amixture of TFA/dichloromethyl (1:1; 6 mL), stirred for 1 hour andevaporated to dryness. (3S)-3-Amino-2-hydroxy-pentanoic acid benzylamidewas obtained as the TFA salt and used without further purification.

Reference 84-(4-Methylsulfonylamino-phenyl)-4-oxo-2-benzylsulfonylmethyl -butyricacid

3-Methylene-dihydro-furan-2,5-dione (2 g, 17.8 mmol) andN-phenyl-methylsulfonamide (1.53 g, 8.92 mmol) were dissolved inanhydrous 1,2-dichloroethane. Aluminum trichloride (4.76 g, 35.7 mmol)was added and the mixture was stirred at 50° C. for 16 hours. Followingdilution with ethyl acetate (400 mL), the solution was washed with 1Naqueous HCl, water and brine, dried with magnesium sulfate andevaporated. The product,4-(4-methylsulfonylamino-phenyl)-2-methylene-4-oxo-butyric acid (1.70g), was crystallized from ethylacetate/hexane.

4-(4-Methylsulfonylamino-phenyl)-2-methylene-4-oxo-butyric acid (800 mg,2.83 mmol) was dissolved in DMF (5 mL). Benzyl mercaptan (0.5 mL, 4.25mmol) and DMAP (200 mg, 1.6 mmol) were added. The mixture was stirred atambient temperature for 16 hours. Methanol (200 mL) was added and, undervigorous stirring, a saturated aqueous solution of Oxone® (15 g, 24.4mmol) was added in one portion. Stirring was continued for 2 hours.Methanol was removed under vacuum and the aqueous residue was dilutedwith 100 mL water. The crystallized product,4-(4-Methylsulfonylamino-phenyl)-4-oxo-2-benzylsulfonylmethyl-butyricacid (380 mg), was filtered, washed with water, and dried under vacuum.

Reference 9 3-Biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid

Sodium hydride (60% in oil, 1.36 g, 34 mmol) was dissolved in anhydrousethanol (50 mL) under ice cooling. After the H₂ evolution ceased,diethylmalonate (5.15 mL, 34 mmol) was added and stirring was continuedfor 30 minutes at ambient temperature. Then 3-bromobenzyl bromide (4.24g, 16.96 mmol) was added and stirring was continued for 2 hours. Thereaction mixture was acidified with 1N aqueous HCl and extracted withethyl acetate (3×150 mL). The combined organic layers were washed withbrine, dried with magnesium sulfate and evaporated. The excessdiethylmalonate was removed under high vacuum.

The crude product was dissolved in ethanol (50 mL) and 1N aqueous NaOH(20 mL) was added. After stirring for 16 hours, the mixture wasacidified with 1N aqueous HCl and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried with magnesiumsulfate and evaporated.

The crude monoacid was dissolved in 1,4-dioxane (20 mL). Diethylamine(2.48 mL, 24 mmol) was added and the solution was cooled to 0° C.Formaldehyde solution (37% in water, 2.44 mL) was added and stirring wascontinued for 24 hours at ambient temperature. After dilution with ethylacetate (300 mL), the solution was washed with water, and brine, driedwith magnesium sulfate and evaporated. The crude product,2-(3-bromo-benzyl)-acrylic acid ethyl ester, was dissolved in ethanol(20 mL). Benzylmercaptan (2 mL, 17 mmol) and triethylamine (4 mL) wereadded. After stirring for 16 hours, 1N aqueous NaOH (50 mL) was addedand enough 1,4-dioxane to get a homogenous solution. The reactionmixture was warmed to 50° C. for 5 hours. All organic solvents wereremoved under vacuum, and the aqueous residue was acidified to pH 1 with1N aqueous HCl. The product was extracted with ethyl acetate (3×150 mL).The combined organic layers were washed with brine, dried with magnesiumsulfate and evaporated. The residue was dissolved in methanol (250 mL)and Oxone® (35 g) was added. The reaction mixture was stirred at ambienttemperature for 2 hours. Methanol was removed under vacuum. Theprecipitated product was filtered, washed with water, and dried undervacuum. Recrystallization from chloroform gave3-(3-Bromo-phenyl)-2-benzylsulfonylmethyl-propionic acid (2.43 g) aswhite solid.

3-(3-Bromo-phenyl)-2-benzylsulfonylmethyl-propionic acid (0.5 g, 1.26mmol) was dissolved in toluene (20 mL) and ethanol (5 mL).Tetrakistriphenylphosphine palladium (146 mg, 0.126 mmol) was added andthe mixture was stirred at ambient temperature under nitrogen for 30minutes. Powdered potassium carbonate (870 mg, 6.3 mmol) andphenylboronic acid (200 mg, 1.64 mmol) were added, and the reactionmixture was heated at 75° C. for 2 hours. After cooling, the mixture wasacidified with 1N aqueous HCl and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine, dried withmagnesium sulfate and evaporated. The acid was purified by flashchromatography on silica gel (ethyl acetate/hexane; 1:1) to yield3-biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (0.40 g).

Reference 10 3-Acetylsulfanyl-2-benzylsulfanylmethyl-propionic acid

2-Bromomethylacrylic acid (3.00 g, 18.1 mmol) was dissolved in methanol(100 mL), cooled on an ice bath and treated with benzyl mercaptan.Aqueous sodium hydroxide (1N, 39.8 mL) was added dropwise and thereaction mixture was allowed to adjust to room temperature with stirringfor 23 hours. Methanol was removed by rotary evaporation at reducedpressure and water (100 mL) was added to the residue, which was thenwashed with ether. The aqueous layer was cooled on ice and acidified topH 2.5. The precipitated solid was isolated by filtration and dried togive 2-benzylsulfanylmethyl-acrylic acid (3.346 g, 89%).

A solution of 2-benzylsulfanylmethylacrylic acid (0.208 g) in methylenechloride (2.5 mL) was treated with thiolacetic acid and stirred at roomtemperature for 72 hours. The reaction mixture was diluted with ethylacetate (50 mL) and then washed twice with water and once with saturatedaqueous sodium chloride. After drying over magnesium sulfate the solventwas removed by rotary evaporation and the residue chromatographed onsilica gel eluting with an ethyl acetate/hexane/acetic acid mixture toproduce 3-acetylsulfanyl-2-benzylsulfanylmethyl-propionic acid (0.208g).

Reference 11 (S)-2-Amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-one

3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol)was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), andN-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethyl (10 mL) wasadded and then 4-methylmorpholine (1 mL). The mixture was stirred atambient temperature for 16 hours. After dilution with ethyl acetate (200mL), the solution was washed with water (30 mL), saturated aqueousNaHCO₃ solution and brine, dried with MgSO₄ and evaporated under vacuum.The crude product was dissolved in pyridine (10 mL) and heated at 80° C.for 15 hours. The pyridine was evaporated under vacuum and the residuewas purified by flash chromatography on silica gel (eluent: ethylacetate) to yield 290 mg (0.83 mmol). The oxadiazole (145 mg, 0.41 mmol)was dissolved in CH₂Cl₂ (4 mL) and TFA (4 mL) was added. After stirringfor 1 hour, the mixture was evaporated to dryness to yield(S)-2-Amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-one.

Reference 12 2-Amino-1-(2-phenyl-[13]dithian-2-yl)-hexan-1-ol

2-phenyl-1,3-dithiane (Aldrich) (3.79 g; 19.3 mmol) was mixed with drydistilled THF (20 mL) under a nitrogen atmosphere. The solution wascooled to −60° C. and n-butyl lithium (1.6M in pentane, 1.56 mmol, 9.74mL) was added slowly by syringe. The reaction mixture was warmed to −20°C. and held at that temperature for 30 minutes, and then held at −10° C.for 15 minutes. The yellow solution was cooled to −78° C. and(1-Formyl-pentyl)-carbamic acid tert-butyl ester (1.6 g, 1.4 mmol, in 5ml THF) was added rapidly (over 20 seconds) and 60 seconds later amixture of 2 mL acetic acid and 5 mL THF was added rapidly. Afterwarming to 23° C. the solution was concentrated at reduced pressure.Excess 2-phenyl-1,3-dithiane was removed by its crystallization awayfrom the desired product using a minimum of ethyl acetate in hexane. Themother liquors were concentrated and chromatographed using ahexane-ethyl acetate gradient to afford 1.7 g of{1-[Hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acidtert-butyl ester. (56% yield).

To {1-[Hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamicacid tert-butyl ester (608 mg, 1.47 mmol) in 2.7 mL dioxane at 10° C.was added hydrochloric acid (2.7 mL, 4M in dioxane). The solution waswarmed to 23° C. After 3 hours the solution was diluted with 5 mltoluene and concentrated under reduced pressure. The gummy solid waswashed with diethyl ether resulting in the hydrochloride salt of2-amino-1-(2-phenyl-[1,3]dithian-2-yl)-hexan-1-ol, 414 mg, 82% as a freeflowing solid after removal of excess ether under reduced pressure.

Reference 13 3-Amino-4-hydroxo-pyrrolidine-1-carboxylic acid tert-butylester

6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester(12.1 g, 65.3 mmol) was dissolved in a 8:1 methanol/water mixture (108mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) wasadded and the mixture was heated at 60° C. overnight. After dilutionwith ether (500 mL), the mixture was washed with saturated aqueousNaHCO₃ (200 mL) and brine (200 mL), dried with MgSO₄ and evaporatedunder vacuum. The crude product was dissolved in methanol (200 mL). 10%Palladium on activated carbon (1.5 g) was added and the mixture wasstirred at ambient temperature under a hydrogen atmosphere until TLCanalysis showed the disappearance of the starting material. The mixturewas filtered through a pad of Celite and evaporated to dryness undervacuum. The product was purified by flash chromatography on silica gel.Eluent: 5% methanol in ethyl acetate to 20% methanol, 3% triethylaminein ethyl acetate. Yield: 4.3 g of3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester asyellowish solid.

Reference 14 2-Amino-2-methyl-1-oxazolo[4,5-b]pyridin-2-yl-propan-1-one

2-amino-2-methyl-1-propanol (17.8 g, 200 mmol) was dissolved in amixture of water and 100 ml dioxane and cooled to 0° C. NaOH (8 g, 200mmol) and di-t-butyl-dicarbonate (52.4 g, 240 mmol) were added and thereaction was allowed to warm to room temperature with stirring for 2hours. After removing the dioxane, the residue was extracted with EtOAc,washed with brine, dried with anhydrous MgSO₄, filtered and concentratedto yield 35 g of product.

A solution of oxylyl chloride (15.24 g, 120 mmol) in 200 ml of MeCl₂ wasstirred and cooled to −60° C. followed by the drop wise addition ofdimethylsulfoxide (19.7 g, 252 mmol) in 60 ml of MeCl₂. After 10minutes, a solution of 2-bocamino-2-methyl-1-propanol (18.9 g, 100 mmol)in 60 ml of MeCl₂ was added drop wise at −70° C. The reaction mixturewas allowed to warm to −40° C. for 10 minutes followed by cooling to−70° C. before the addition of a solution of triethylamine (28.28 g, 280mmol) in 60 ml of MeCl₂. The reaction mixture was allowed to warm toroom temperature over a two-hour period and 40 ml of saturated sodiumdihydrogen phosphate was added. The organic layer was washed with brineand dried over MgSO₄. The solvent was removed to yield 17.3 g ofaldehyde.

A mixture of 2-amino-3-hydroxy pyridine (11 g, 100 mmol),triethylorthoformate (80 ml) and p-toluenesulfonic acid (61 mg) washeated at 140° C. for 8 hours. Excess triethylorthoformate was removedunder vacuum. The product was crystallized from ethyl acetate to yield 9g of pyridyloxazole; H¹ NMR (DMSO-δ): 9.26 (1H, s), 8.78 (1H, d), 8.45(1H, d), 7.7(1H, dd); MS: 120.8 (M+1).

To a stirred solution of the pyridyloxazole (2.4 g, 20 mmol) in THF (100ml) was added n-BuLi (1.6M solution in 12.5 ml of hexane) drop wiseunder N₂ at −78° C. After 1 hour, MgBr.Et₂O (5.16 g, 20 mmol) was addedand the reaction mixture was allowed to warm to −45° C. for 1 hourbefore being treated with 2-boc-amino-2-methyl-propanyl-aldehyde (2.24g, 12 mmol) in THF (20 ml). The reaction mixture was stirred for 1 hour,quenched with saturated NH₄Cl, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄ and concentrated.The residue was purified by silica gel column chromatography to yield2-boc-amino-2-methyl-1-(5-pyridyloxazole-2-yl)-1-propanol (1.18 g); H¹NMR (DMSO-δ): 8.5(1H, d,d, J=1.46 Hz, J=4.94 Hz), 8.14(1H, d,d, J1.49Hz, J=8.16 Hz), 7.41(1H, d,d, J=4.7 Hz, J=8.18 Hz), 7.1-6.8(1H, d, d),6.53(1H, br, NH), 6.24, 6.22(1H, s,s, OH), 5.23, 5.21(1H, s,s, 1.37(3H,s, CH3), 1.33(9H, s, 3×CH3), 1.22(3H, s, CH3); MS: 308.2 (M+1).

2-Boc-amino-2-methyl-1-(5-pyridyloxazole-2-yl)-1-propanol (156 mg, 0.508mmol) and MeCl₂ (5 ml) were mixed and TFA (0.5 ml) was added at roomtemperature. After stirring for 1 hour, the solvent and excess TFA wereremoved under vacuum to produce2-amino-2-methyl-1-oxazolo[4,5-b]pyridin-2-yl-propan-1-one TFA salt (165mg).

Reference 152-Amino-1-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-butan-1-one

(S)-(+)-2-amino-1-butanol (50 g, 561 mmol) in 200 ml of water and 200 mldioxane was cooled to 0° C. and mixed with NaOH (26.9 g, 673 mmol) anddi-t-butyl-dicarbonate (146.96 g, 673 mmol). After the addition, thereaction was allowed to warm to room temperature. The reaction mixturewas stirred for 2 hours. After removing the dioxane, the residue wasextracted with EtOAc, then washed with brine and dried with anhydrousMgSO₄, filtered and concentrated. Without further purification, thecrude product (120 g) was used for next step reaction.

A solution of oxylyl chloride (40.39 g, 265 mmol) in 700 ml of MeCl₂ wasstirred and cooled to −60° C. Dimethylsulfoxide (51.7 g, 663 mmol) in100 ml of MeCl₂ was added drop wise. After 10 minutes a solution of(S)-2-boc-amino-1-butanol (50 g, 265 mmol) in 100 ml of MeCl₂ was addeddrop wise at −70° C. The reaction mixture was allowed to warm to −40° C.for 10 minutes and then cooled to −70° C. again. A solution oftriethylamine (74.9 g, 742 mmol) in 100 ml of MeCl₂ was added. Thereaction mixture was allowed to warm to room temperature over 2 hours.100 mls of saturated sodium dihydrogen phosphate was added, and then theorganic layer was washed with brine and dried over MgSO₄. The solventwas removed to yield 45 g of (1-formyl-propyl)-carbamic acid tert-butylester; H¹ NMR (DMSO-δ): 9.4(1H, s), 7.29(1H, br.), 3.72(1H, m), 1.69(2H,m), 1.4-1.2(9H, s), 0.86(3H, t).

A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate(30 ml) was heated to reflux for 8 hours. Excess hydrazine and waterwere removed under vacuum. The residue was extracted with n-butanol,dried with Na₂SO₄. Excess n-butanol was removed to yield 45 g ofhydrazide.

A mixture of above hydrazide (45 g), triethylorthoformate (146 ml) andp-toluenesulfonic acid (61 mg) was heated at 140° C. for 8 hours. Excesstriethylorthoformate was removed under vacuum. The product was purifiedby silica gel column chromatography to yield 4.6 g of2-methoxymethyl-1,3,4-oxadiazole; H¹ NMR (DMSO-δ): 9.21(1H, s), 4.63(2H,s), 3.27(3H, s).

To a stirred solution of 2-methoxymethyl-1,3,4-oxadiazole (4.6 g, 40mmol) in THF (100 ml) was added n-BuLi (1.6M solution in 25.2 ml ofhexane) drop wise under N₂ at −78° C. After 1 hour, MgBr.Et₂O (10.4 g,40.3 mmol) was added and the reaction mixture was allowed to warm to−45° C. for 1 hour before being treated with 2-boc-amino-propanylaldehyde (5.28 g, 28.25 mmol) in THF (20 ml). The reaction mixture wasstirred for 1 hour, quenched with saturated NH₄Cl, and extracted withethyl acetate. The organic layer was washed with brine, dried with MgSO₄and concentrated. The residue was purified by silica gel columnchromatography to yield2-boc-amino-1-(5-methoxymethyl-1,3,4-oxadiazole-2-yl)-1-propanol (500mg); H¹ NMR (DMSO-δ): 6.7(½H, d, NH, diastereomeric), 6.5(½H, d, NH,diastereomeric), 6.2(½H, d, OH, diastereomeric), 6.0(½H, d, OH,diastereomeric), 4.83-4.79(1H, m), 4.55(2H, s), 4.05-3.5(1H, m),3.31(3H, s), 1.9-1.4(2H, m), 1.4-1.2(9H, m), 0.85-0.81(3H, m); MS:300.4(M−1), 302.4(M+1).

2-Boc-amino-1-(5-methoxymethyl-1,3,4-oxadiazole-2-yl)-1-propanol (500mg, 1.66 mmol), and MeCl₂ (5 ml) were mixed and TFA (0.5 ml) was addedat room temperature. After stirring for 1 hour, the solvent and excessTFA were removed under vacuum to produce2-amino-1-(5-methoxymethyl-[[3,4]oxadiazol-2-yl)-butan-1-one TFA salt(340 mg).

Reference 16 2-Amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol

A mixture of the benzylhydrazide (22.5 g, 165 mmol),triethylorthoformide (150 ml) and p-toluenesulfonic acid (300 mg) washeated at 120° C. for 12 hours. Excess triethylorthoformide was removedunder vacuum and the residue was purified by silica gel columnchromatography to produce oxadiazole (14.5 g); H¹ NMR (DMSO-δ): 9.34(1H, s), 8.05-7.98 (2H, m), 7.68-7.55 (3H, m); MS: 147.4 (M+1).

To a stirred solution of the oxadiazole (10 g, 68.5 mmol) in THF (100ml) was added n-BuLi (1.6M solution in 42.8 ml of hexane) drop wiseunder N₂ at −78° C. After 1 hour, MgBr.Et₂O (17.69 g, 68.5 mmol) wasadded and the reaction mixture was allowed to warm to −45° C. for 1 hourbefore being treated with 2-boc-amino-butyl-aldehyde (7.8 g, 41 mmol) inTHF (20 ml). The reaction mixture was stirred for 1 hour, quenched withsaturated NH₄Cl, and extracted with ethyl acetate. The organic layer waswashed with brine, dried with MgSO₄ and concentrated. The residue waspurified by silica gel column chromatography to yield2-(2-boc-amino-1-hydroxydutyl)-5-benzyl-1,3,4-oxadiazole (9.7 g); H¹ NMR(DMSO-δ): 8-7.9(2H, m), 7.8-7.7(3H, m), 6.8-6.6(1H, d,d, NH,diastereomeric), 6.4-6.1(1H, d,d, OH, diastereomeric), 5-4.4(1H, m),1.9-1.3(2H, m), 1.3-1.1(9H, s, s), 0.84(3H, t); MS: 334.5(M+1).

2-(2-Boc-amino-1-hydroxybutyl)-5-benzyl-1,3,4-oxadiazole (505 mg, 1.5mmol) and MeCl₂ (5 ml) were mixed and TFA (1 ml) was added at roomtemperature. After stirring for 1 hour, the solvent and excess TFA wereremoved under vacuum to produce 530 mg of2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt.

Reference 17 2-Amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-one

A mixture of 2-amino-3-hydroxy pyridine (25 g, 227 mmol),triethylorthoformate (75 ml) and p-toluenesulfonic acid (61 mg) washeated at 140° C. for 8 hours. Excess triethylorthoformate was removedunder vacuum. The product was crystallized from ethyl acetate to yield22.5 g of pyridyloxazole; H¹ NMR (DMSO-δ): 9.26 (1H, s), 8.78 (1H, d),8.45 (1H, d), 7.7(1H, dd); MS: 120.8 (M+1).

Pyridyloxazole (600 mg, 5 mmol) in 30 ml THF was cooled to 0° C. beforethe addition of isopropanyl magnesium chloride (2M in THF, 2.5 ml, 5mmol). After stirring for 1 hour at 0° C., the aldehyde (573 mg, 3 mmol)in 20 ml THF was added. The ice bath was removed and the reactionallowed to warm to room temperature. The reaction mixture was stirredfor 2 hours and quenched with saturated ammonium chloride solution.Excess THF was removed and the residue was extracted with EtOAc, washedwith brine, dried with anhydrous MgSO₄, filtered and concentrated. Thecrude residue was purified by chromatography to yield 383 mg product; H¹NMR (DMSO-δ): 8.42(1H, m), 8.18(1H, m), 7.3(1H, m), 6.8, 6.6(1H, dd, d,OH, diastereomeric), 6.3, 6.02(1H, d, d, NH, diastereomeric), 4.82,4.5(1H, m, m, diastereomeric), 1.8-1.3(2H, m), 1.2, 1.05(9H, s,s,diastereomeric), 0.89(3H, m); MS: 306.2(M−1), 308.6(M+1).

To a stirred solution of the pyridyloxazole (12 g, 100 mmol) in THF (300ml) was added n-BuLi (1.6M solution in 62.5 ml of hexane) drop wiseunder N₂ at −78° C. After 1 hour, MgBr.Et₂O (25.8 g, 100 mmol) was addedand the reaction mixture was allowed to warm to −45° C. for 1 hourbefore being treated with 2-boc-amino-butyl-aldehyde (11.46 g, 60 mmol)in THF (50 ml). The reaction mixture was stirred for 1 hour, quenchedwith saturated NH₄Cl, and extracted with ethyl acetate. The organiclayer was washed with brine, dried with MgSO₄ and concentrated. Theresidue was purified by silica gel column chromatography to yield2-boc-amino-1-(5-pyridyloxazole-2-yl)-1-butanol (14.1 g).

2-Boc-amino-1-(5-pyridyloxazole-2-yl)-1-butanol (311 mg, 1 mmol) andMeCl₂ (5 ml) were mixed and TFA (1 ml) was added at room temperature.After stirring for 1 hour, the solvent and excess TFA were removed undervacuum to produce 355 mg of2-amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-one TFA salt.

Reference 182-Amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-one

A mixture of the isonicotinic hydrazide (13.7 g, 100 mmol),triethylorthoformate (60 ml) and p-toluenesulfonic acid (30 mg) washeated at 130° C. for 12 hours. Excess triethylorthoformate was removedunder vacuum. The product was crystallized from ethyl acetate to yield14.8 g; H¹ NMR (DMSO-δ): 9.46 (1H, s), 8.8 (2H, dd), 7.9 (2H, dd).

To a stirred solution of the oxadiazole (11.5 g, 78.2 mmol) in THF (300ml) was added 5 ml HMPA and n-BuLi (1.6M solution in 48.9 ml of hexane)drop wise under N₂ at −78° C. After 1 hour, MgBr.Et₂O (20.2 g, 78.2mmol) was added and the reaction mixture was allowed to warm to −45° C.for 1 hour before being treated with 2-boc-amino-butylldehyde (9.7 g,50.8 mmol) in THF (50 ml). The reaction mixture was stirred for 1 hour,quenched with saturated NH₄Cl, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄ and concentrated.The residue was purified with silica gel column chromatography to yield2-bocamino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (3.5 g);H¹ NMR (DMSO-δ): 8.85-8.8(2H, m), 7.95-7.8(2H, m), 6.66(1H, d,),6.19(1H, d), 4.96(1H, t), 3.75-3.6(1H, m), 1.72-1.6(1H, m), 1.5-1.35(1H,m), 1.27(9H, s), 0.87(3H, t); MS: 333.2 (M−1), 335.4 (M+1).

2-Bocamino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (334 mg,1 mmol) and MeCl₂ (5 ml) were mixed and TFA (0.5 ml) was added at roomtemperature. After stirring for 1 hour, the solvent and excess TFA wereremoved under vacuum to produce 350 mg of2-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-one TFA salt.

Reference 192-Amino-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-butan-1-one

To a stirred solution of the 3-[1,3,4]oxadiazol-2-yl-pyridine (5 g, 34mmol) in THF (100 ml) was added 5 ml HMPA and n-BuLi (1.6M solution inhexane, 21.25 ml) drop wise under N₂ at −78° C. After 1 hour, MgBr.Et₂O(8.77 g, 34 mmol) was added and the reaction mixture was allowed to warmto −45° C. for 1 hour before being treated with 2-boc-amino-butylldehyde(4.22 g, 22.1 mmol) in THF (20 ml). The reaction mixture was stirred for1 hour, quenched with saturated NH₄Cl, and extracted with ethyl acetate.The organic layer was washed with brine, dried with MgSO₄ andconcentrated. The residue was purified with silica gel columnchromatography to yield2-boc-amino-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (1.5 g);H¹ NMR (DMSO-d): 9.2-9.1(1H, d), 8.82-8.76(1H, m), 8.4-8.3(1H, m),7.68-7.6(1H, m), 6.78, 6.65(1H, dd, NH, diastereomeric), 6.38, 6.16(1H,d,d, OH, diastereomeric), 3.8-3.6(1H, m), 1.9-1.2(2H, m), 1.3, 1.1 (9H,s,s,), 0.84(3H, t); MS: 331.2 (M−1).

2-Boc-amino-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (167 mg,0.5 mmol) and MeCl₂ (5 ml) were mixed and TFA (0.5 ml) was added at roomtemperature. After stirring for 1 hour, the solvent and excess TFA wereremoved under vacuum to produce 180 mg of2-amino-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-butan-1-one TFA salt.

Reference 20 2-Amino-1-benzooxazol-2-yl-butan-1-one

Benzoxazole (600 mg, 5 mmol) in 20 ml THF was cooled to −5° C. andisopropyl magnesium chloride (2 M in THF, 2.5 ml, 5 mmol) was added.After stirring for 1 hour at −5° C., the aldehyde (561 mg, 3 mmol),prepared as in reference 15, in 10 ml THF was added. The reaction wasallowed to warm to room temperature with stirring for 2 hours. Thereaction was quenched with saturated ammonium chloride solution, excessTHF solvent removed. The residue was extracted with EtOAc, washed withbrine, dried with anhydrous MgSO₄, filtered and concentrated. The cruderesidue was purified by chromatograph to yield 688 mg product (75%);LC-MS: 305.2 (M−1), 307.0 (M+1); H¹NMR (DMSO-d₆): 7.72-7.6 (2H, m),7.38-7.28 (2H, m), 6.7 (d)-6.52(d) (1H, NH, diastereomeric),6.12(d)-5.92 (d) (1H, OH, diastereomeric), 4.81(dd)-4.57(dd) (1H,CH—OH), 3.74 (1H, m), 1.9-1.6 (1H, m), 1.6-1.3 (1H, m), 1.25(s)-1.1(s)(9H, diastereomeric), 0.85 (3H, t).

[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butylester (275 mg, 0.89 mmol) and MeCl₂ (5 ml) were mixed and TFA (1 ml) wasadded at room temperature. After stirring for 1 hour, the solvent andexcess TFA were removed under vacuum to produce 260 mg of2-amino-1-benzooxazol-2-yl-butan-1-one TFA salt.

Reference 21 2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid

A 0.05 M solution of1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-butane-1,4-dione(1 g) in 3:1-THF/H₂O was treated at 0° C. with 8 equivalents of 30% H₂O₂followed by 2.0 equivalents of LiOH. The resulting mixture was stirredat 0-25° C. until the substrate had been consumed (approximately 1hour). The excess peroxide was quenched at 0° C. with a 10% excess of1.5 N aqueous Na₂SO₃. After buffering to pH 9-10 with aqueous NaHCO₃ andevaporation of the THF, the oxazolidone chiral auxiliary was recoveredby MeCl₂ extraction. The carboxylic acid was isolated by EtOAcextraction of the acidified (pH 1-2) aqueous phase, then recrystallizedfrom EtOAc and hexane to yield 0.58 g of2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid; H¹ NMR (DMSO-δ):12(1H, s, COOH), 3.6-3.3(8H, m), 2.8-2.3(3H, m), 1.8-1.1(11H, m),0.9-0.7(2H, m); MS: 282.2(M−1), 284.1 (M+1).

Reference 22 2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyric acid

(S)-(−)-4-Benzyl-2-oxazolidinone (5 g, 28.2 mmol) was dissolved in THF(100 mL) and cooled to −78° C. under nitrogen. A 2.5M solution ofn-butyllithium in hexane (12.4 mL) was added with a syringe and themixture was stirred for 30 min. 4-Cyclohexyl-butyryl chloride (5.85 g,31 mmol) was added at −78° C. The mixture was allowed to warm to 0° C.over two hours. 1N HCl (50 mL) was added and the product was extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith saturated aqueous NaHCO₃ (200 mL) and brine (200 mL), dried withMgSO₄ and evaporated under vacuum. The product was recrystallized fromhexane/ether and obtained as a white solid (5.6 g).

A solution of diisopropylamine (1.92 mL, 13.68 mmol) in dry THF (50 mL)was cooled to −20° C. A 2.5M solution of n-butyllithium in hexane (4.4mL) was added with a syringe. The mixture was stirred for 30 min andthen cooled to −78° C. A solution of4-benzyl-3-(4-cyclohexyl-butyryl)-oxazolidin-2-one (3 g, 9.12 mmol) inTHF (10 mL) was added slowly over 3 min. Stirring was continued for 30min, then a solution of 2-Bromo-1-morpholin-4-yl-ethanone (2.28 g, 10.94mmol) in THF (4 mL) was added over 3 min. The mixture was allowed tocome to room temperature over 5 h. 1N HCl (50 mL) was added and theproduct was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ (200 mL) andbrine (200 mL), dried with MgSO₄ and evaporated under vacuum. Theproduct(1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-butane-1,4-dione)was obtained after purification by flash chromatography as a singlediastereomer (2.5 g). ¹H NMR: (CDCl₃) 7.35-7.22 (m, 5H), 4.69-4.62 (m,1H), 4.28-4.10 (m, 3H), 3.76-3.46 (m, 8H), 3.37 (d, J=13.6 Hz, 1H), 2.91(ddd, J=16.4 Hz, J=13 Hz, J=3 Hz, 1H), 2.76 (ddd, J=13.5 Hz, J=11 Hz,J=3 Hz, 1H), 2.51 (dt, J=13.6 Hz, J=3 Hz, 1H), 1.76-0.80 (m, 15H). MS:(M+H)⁺ 457.

1-(4-Benzyl-2-oxo-oxazolidin-3-yl)-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-butane-1,4-dione(2.5 g, 5.48 mmol) was dissolved in a 3:1-THF/H₂O mixture (50 mL) andcooled to 0° C. H₂O₂ (5 mL) was added followed by lithium hydroxydemonohydrate (462 mg, 11 mmol). The mixture was stirred at 0° C. for 30min. Excess peroxide was quenched with 1.5N Na₂SO₃ solution and the THFwas evaporated under vacuum. The chiral auxiliary was removed byextraction with diethyl ether. After acidification to pH 1 the productwas isolated by extraction with ethyl acetate. The combined organiclayers were washed with saturated aqueous NaHCO₃ (200 mL) and brine (200mL), dried with MgSO₄ and evaporated under vacuum. The crude acid((2R)-2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyric acid) wasused for coupling (EDC) and oxidation (Dess-Martin) as described in theexamples, infra.

(2R)-1-((4S)-4-Benzyl-2-oxo-oxazolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-butane-1,4-dionewas prepared by the same procedure as described for reference 22.4-Cyclohexyl-butyryl chloride was substituted by 3-cyclohexyl-propionylchloride. ¹H NMR: (DMSO) 7.35-7.22 (m, 5H), 4.63-4.56 (m, 1H), 4.28 (t,J=8.5 Hz, 1H), 4.17-4.06 (m, 2H), 3.70-3.35 (m, 8H), 2.94 (d, J=13.2 Hz,1H), 2.82 (dd, J=13.2 Hz, J=8 Hz, 1H), 2.72 (dd, J=16 Hz, J=10.4 Hz,1H), 2.51 (dd, J=16 Hz, J=3.2 Hz, 1H), 1.75-0.75 (m, 13H); MS: (M+H)⁺443.

Reference 23 N-Isopropyl-2-benzylsulfonylmethyl-succinamic acid

To a stirring mixture of itacconic anhydride (1.1209 g, 10 mmol) in 10ml of methylene chloride at 0° C. was added drop wise isopropyl amine(0.85 ml, 10 mmol). The reaction was stirred at room temperature for 1hour and the solvent was removed under reduced pressure to give2-(isopropylcarbamoyl-methyl)-acrylic acid. The residue was dissolved in10 ml of DMF, then benzyl mercaptan (1.17 g, 10.0 mmol) and DMAP (122mg, 1 mmol) were added and the reaction was stirred at room temperaturefor overnight. The mixture containing2-benzylsulfanylmethyl-N-isopropyl-succinamic acid was cooled to 0° C.and oxone® (4.9182 g, 8 mmol) in 20 ml of water was added and stirredfor 2 hours at room temperature. More oxone® was added and the reactionwas stirred at room temperature for 18 hours. The reaction was filteredand the white solid was washed with water, ether and dried under highvacuum to give 1.0 grams ofN-isopropyl-2-benzylsulfonylmethyl-succinamic acid, which was usedwithout further purification; LCMS retention time 2:32 minutes: MS+1(328.1).

Reference 244-(4-Methyl-piperazin-1-yl)-4-oxo-2-benzylsulfonylmethyl-butyric acid

To a stirring mixture of itacconic anhydride 1.1209 g, 10 mmol) in 10 mlof methylene chloride at 0° C. was added drop wise methyl piperizine(1.0 g, 10 mmol). The reaction was stirred at room temperature for 1hour and the solvent was removed under reduced pressure to give compound2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-acrylic acid. The residuewas dissolved in 10 ml of DMF, then benzyl mercaptan (1.17 g, 10.0 mmol)and DMAP (122 mg, 1 mmol) were added and heated to 50-60° C. untilreaction turned clear then the reaction was stirred at room temperaturefor overnight. Another 0.59 ml of benzyl mercapton (5 mmol) was addedand the reaction was stirred overnight at room temperature. The mixturecontaining compound2-benzylsulfanylmethyl-4-(4-methyl-piperazin-1-yl)-4-oxo-butyric acidwas cooled to 0° C. and oxone® (6.1378 g, 10 mmol) in 20 ml of water wasadded and stirred for overnight at room temperature. More oxone® wasadded and the reaction was stirred at room temperature for 2 hours. Thereaction was filtered and the product was in the aqueous phase and waspurified on HPLC to give 0.2477 gram of pure4-(4-methyl-piperazin-1-yl)-4-oxo-2-benyzlsulfonylmethyl-butyric acid;LCMS retention time: 1.72 minutes; M+1 (369.3).

Reference 25 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid

Reference 25 was synthesized as described in the following reactionprotocol:

2-(2-Morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl ester (1)

To a solution of n-tetra butyl ammonium hydrogen sulfate (1.18 g, 3.48mmol) and NaOH (560 mg, 13.9 mmol) in water (8 ml) was added a solutionof 4-(2-bromoacetyl morpholine) (1.45 g, 6.97 mmol) and diethyl malonate(1.34 g, 8.36 mmol) in DCM (8 ml). The mixture was stirred at roomtemperature for 3 hours, diluted with water (30 ml) and extracted withDCM (2×30 ml). The organic layer was dried (MgSO₄) and concentrated invacuum. The residue was purified by chromatography (silica) eluting with1:2 v/v ethyl acetate-heptane to give2-(2-morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl ester as acolorless oil (1.19 g, 59%); ¹H NMR (CDCl₃) 4.25 (m, 4H), 4.0 (t, J=7.2Hz, 1H), 3.8-3.45 (m, 8H), 3.0 (d, J=7.4 Hz, 2H), 1.3 (t, J=7.11 Hz,6H).

2-(2-Morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid diethylester (2)

To a mixture of Pd(OAc)₂ (17.5 mg, 0.078 mmol) and PPh₃ (40.9 mg, 0.156mmol) in dry THF (2 ml) under N₂, cinnamyl alcohol (105.1 mg, 0.78 mmol)was added followed by a solution of2-(2-morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl ester (250 mg,0.87 mmol) and NaH (17.4 mg, 0.43 mmol) in dry THF (3 ml). BF₃ (1M inTHF, 1 ml, 1 mmol) was then added and the yellow solution was stirred atroom temperature for 6.5 hours. The mixture was diluted with ethylacetate (50 ml) and washed with 1N HCl (10 ml) and brine (2×20 ml). Theorganic layer was dried (MgSO₄), concentrated in vacuum and purified bychromatography eluting with 1:1 v/v ethyl acetate-heptane mixture togive 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic aciddiethyl ester as a thick, yellow oil (266.5 mg, 85%); ¹H NMR (CDCl₃)7.25 (m, 5H), 6.40 (d, J=15.6 Hz, 1H), 6.1 (dt, J=15.8, 7.7 Hz), 4.2 (q,J=7.1 Hz, 4H), 3.6 (m, 6H), 3.45 (m, 2H), 3.05 (d, J=7.6 Hz, 2H), 3.0(s, 2H), 1.25 (t, J=7.1 Hz, 6H). MS: 404 (MH⁺)

2-(2-Morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic aciddiethyl ester (3)

A solution of2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid diethylester (257 mg, 0.637 mmol) in EtOH (15 ml) was hydrogenated over Pd/C at55 Psi for 7.5 hrs. The catalyst filtered off over a pad of Celite andthe filtrate evaporated under vacuum to give2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic aciddiethyl ester as a light yellow oil (260 mg); ¹H NMR (CDCl₃) 7.4-7.1 (m,5H), 4.20 (q, J=7.1 Hz, 4H), 3.7-3.4 (m, 8H), 3.0 (s, 2H), 2.6 (t, J=7.6Hz, 2H), 2.2 (m, 2H), 2.55 (m, 2H), 1.20 (t, J=7.1 Hz, 6H). MS: 406(MH⁺).

2-(2-Morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acidmonoethyl ester (4)

To a solution of2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic aciddiethyl ester (934 mg, 2.3 mmol) in a 2:1 mixture of ethanol and water(12 ml) LiOH.H₂O (193.3 mg, 4.61 mmol) was added and heated at 40° C.for 19 hrs. Ethanol was evaporated under reduced pressure, the residualaqueous mixture was acidified to pH 1 and extracted with methylenechloride (2×40 ml). The organic extract was dried with MgSO₄ andevaporated under reduced pressure to give2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acidmonoethyl ester as a thick, yellow oil (831 mg); ¹H NMR (CDCl₃) 7.4-7.1(m, 6H), 4.25 (q, J=7.1 Hz, 2H), 3.8-3.4 (m, 8H), 3.20 (d, J=16.4 Hz,1H), 2.9 (d, J=16.4 Hz, 1H), 2.6 (m, 2H), 2.1-1.8 (m, 4H), 1.25 (t,J=7.1 Hz, 3H). MS: 378 (MH⁺).

2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl ester (5)

A Solution of2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acidmonoethyl ester (809 mg, 2.14 mmol) in toluene (25 ml) was heated underreflux for 23 hours. The colorless solution was concentrated underreduced pressure, the residue was taken up in diethyl ether (50 ml),washed with saturated NaHCO₃ and dried over MgSO₄. The solvent wasevaporated under reduced pressure to give2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl ester asyellow oil (617 mg); ¹H NMR (CDCl₃) 7.3-7.1 (m, 5H), 4.2 (m, 2H),3.8-3.4 (m, 8H), 3.0 (m, 1H), 2.75 (dd, J=15.9, 9.4 Hz, 1H), 2.65 (m,2H), 2.35 (dd, J=15.9, 5.1 Hz, 1H), 1.8-1.55 (m, 4H), 1.29 (t, J=7.1 Hz,3H). MS: 334 (MH⁺).

2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid (6)

To a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid ethyl ester (604 mg, 1.81 mmol) in a 2:1 mixture of MeOH—H₂O (12ml) LiOH.H₂O (228 mg, 5.43 mmol) was added and stirred overnight at roomtemperature. Ethanol was removed under reduced pressure, residue dilutedwith water (40 ml) and washed with ether. The aqueous layer wasacidified to pH1 with 1N HCl and extracted with diethyl ether (3×25 ml).The combined organic extracts were dried with MgSO₄ and concentratedunder reduced pressure to give2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as a whitesolid (492 mg); ¹H NMR (CDCl₃) 8.0-7.5 (1H), 7.4-7.1 (m, 5H), 3.8-3.4(m, 8H), 3.0 (m, 1H), 2.8 (dd, J=16.4, 9.6 Hz, 1H), 2.65 (t, J=7.2 Hz,2H), 2.40 (dd, J=16.4, 4.3 Hz, 1H), 1.9-1.5 (m, 4H). MS: 306 (MH⁺).

Reference 26 2-Amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol

Reference 26 was synthesized as described in the following reactionprotocol:

{1-[Hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acidtert-butyl ester (2)

A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic acid tert-butylester (9.53 g, 44 mmol) in methanol (80 ml) was cooled to 0° C. andtreated successively with hydroxylamine hydrochloride (3.05, 44 mmol) inmethanol (80 ml) and 25% sodium methoxide solution in methanol (10.2ml). Stirred at 0° C. for 5 minutes, cold bath removed and the reactionmixture stirred at room temperature for 5 hours. Methanol evaporated offunder reduced pressure, crude partitioned between ethyl acetate andwater. Organic layer separated, dried (MgSO₄) and evaporated underreduced pressure to give yellow oil. Purified by mplc, eluting with amixture of ethyl acetate-heptane to give the title compound as whitesolid (3.5 g); MS: M(H⁺) 248.

{1-[Hydroxy-(N-benzoyloxycarbamimidoyl)-methyl]-propyl}-carbamic acidtert-butyl ester (3)

A solution of{1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acidtert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethyl (125 ml) wastreated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol),HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirredat room temperature overnight. Reaction mixture was washed withsaturated sodium bicarbonate solution and then water and dried overNa₂SO₄. Solvent evaporated under reduced pressure, crude purified bymplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptanemixture to give yellow solid (850 mg); MS: MH⁺ 352.

2-Amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol (5)

A solution of (3) (1.5 g, 4.3 mmol) in diglyme was heated at 150° C. ina microwave (Smith Creator, S00219) for 40 minutes. Solvent evaporatedunder vacuum in Genevac Evaporator at 80° C. for 3 hours to give a brownsolid. This was taken in dichloromethyl (40 ml) and treated withtrifluoroacetic acid at room temperature for 2 hours. Solvent evaporatedto dryness under reduced pressure, crude taken in water, washed withDCM, aqueous layer basified with 1M NaOH solution and extracted withdichloromethyl. Organic layer dried over Na₂SO₄ to give pale brown solid(300 mg); ¹HNMR (CDCl₃) 8.14-8.10 (m, 2H), 7.59-7.47 (m, 3H), 4.83 &4.65 (d, J=5 Hz, 1H), 3.18-3.05 (2m, 1H), 1.71-1.20(m, 2H), 1.05-0.97(dt, J=7.2 Hz, 3H).

Reference 273-Benzylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (27a)

3-(Propane-1-sulfonyl)-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid(27b)

Compounds 27a and 27b were synthesized according to the followingprotocol:

2-(Tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethyl ester (1)

NaH added to a solution of 4-hydroxy tetrahydropyran (5 g, 49 mmol) inTHF (40 ml) stirred at room temperature for 30 minutes. A solution ofethyl 2-(bromomethyl) acrylate (9.6 g, 49 mmol) in THF (30 ml) was addedand stirred at room temperature overnight. Reaction mixture cooled inice, quenched with saturated NH₄Cl solution and extracted with ethylacetate. Organic extracts dried, (Na₂SO₄) and purified by mplc elutingwith 1:9 to 2:8 v/v ethyl acetate-heptane mixture to give the titlecompound as yellow oil (6.56 g, 61%). MS: MH⁺ 215; LCMS retention time3.29 minutes.

3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid ethylester (2a)

A suspension of 2-(tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethylester (2.2 g, 10.2 mmol) in ethanol (100 ml) was treated with a solutionof NaHCO₃ (0.86 g, 10.2 mmol) in water ml (10 ml) and benzyl mercapton(1.21 ml, 10.2 mmol) at room temperature overnight. Ethanol evaporatedoff under reduced pressure, crude partitioned between ethyl acetate andwater, organic layer separated and purified by mplc eluting with 1:9 to2:8 v/v ethyl acetate-heptane mixture to give the title compound as paleyellow oil (1.27 g). MS: 339 (MH⁺); LCMS (Protocol B) retention time 4.3minutes.

By using ethylmercapton3-ethylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid ethylester (2b) was similarly prepared; MS: 281 (MH⁺); LCMS retention time3.9 minutes.

3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (3a)

A solution of3-benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid ethylester (1.27 g) in ethanol (30 ml) was treated with 2N NaOH (9.4 ml)overnight. Usual water work up gave the title compound as white solid;MS: 333 (M+Na), 311 (M+1); LCMS retention time 3.7 minutes.

3-Ethylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (3b)was similarly prepared by using3-ethylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid ethylester.

3-Benzylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (27a)

A solution of3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (1.16g, 3.7 mmol) in a mixture of MeOH (10 ml) and water (30 ml) was treatedoxone (3.5 g, 5.6 mmol) overnight. Methanol evaporated off under reducedpressure, aqueous layer extracted with ethyl acetate, dried (Na₂SO₄) andevaporated under reduced pressure to give the title compound as whitesolid (1.36 g); MS: 365 (M+Na), 343 (MH⁺); LCMS retention time 3.1minutes.

3-ethylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (27b)was similarly prepared from3-ethylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid; MS:303 (M+Na), 281 (MH⁺); LCMS retention time 2.3 minutes.

Reference 28 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid(28a);2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (28b);2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acid(28c); and2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (28d)

4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (28a)2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (28b)2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acid(28c)2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (28d)

Compounds 28a, b, c and d were synthesized according to the followingprotocol:

Synthesis of 2-(2-morpholin-4-yl-2-oxo-ethyl)-acrylic acid (1)

Morpholine (20 mL, 228.6 mmol) was slowly added to a stirring solutionof itaconic anhydride (25.1 g, 228.6 mmol) suspended in dichloromethylat 0° C. The reaction mixture was allowed to slowly warm to roomtemperature. Upon completion (LCMS), volatiles were removed by vacuumunder reduced pressure. Crude yield: 44.96 g, 99%. Product was usedwithout further purification.

Synthesis of 2-Acetylsulfanylmethyl-4-morpholin-4-yl-4-oxo-butyric acid(2)

2-(2-morpholin-4-yl-2-oxo-ethyl)-acrylic acid (55.19 g, 277.0 mmol) wasdissolved in 120 mL DMF and set to stir at room temperature. Potassiumthioacetate (25 g, 219.0 mmol) was added in one portion, and thereaction mixture was allowed to stir at ambient temperature for 20hours. Upon completion (LCMS), DMF was removed by vacuum under reducedpressure. Crude Yield: 75 g. Percent Purity (LCMS): 40%. The crudeproduct was used without further purification.

Synthesis of 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid(28a)

4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (8.078 g,29.37 mmol) was dissolved in 100 mL dry EtOH and set to stir at roomtemperature. NaOH pellets (3.52 g, 88.0 mmol) were added in one portion,and the reaction mixture was allowed to stir for 10 minutes. Benzylbromide (3.18 mL, 26.7 mmol) was then added, and the reaction mixturewas allowed to stir at ambient temperature for 20 hours. Upon completion(LCMS), the reaction mixture was diluted with water and the pH waslowered to ˜pH2. The reaction mixture was then washed 3× with EtOAc. Theorganic phase was concentrated in vacuo and then diluted with 200 mLaqueous MeOH. Oxone® (10.78 g, 16.58 mmol) was added in one portion andthe reaction was stirred at room temperature for 4 hours. Conversion ofsulfide to sulfone was monitored via LCMS. Upon completion, reaction wasquenched by the addition of sodium thiosulfate. Salts were filtered andthe reaction mixture was washed 3× with ethyl acetate and dried oversodium sulfate. The organics were evaporated by vacuum under reducedpressure. The crude solid was crystallized from EtOAc. Yield 1.3 gPercent Purity (NMR): 99%. m/z (LCMS) M⁺ 356.01. δ_(H) 12.6 (1H, br s),7.4 (5H, m), 4.5 (2H, s), 3.5 (4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.2(2H, d), 2.75 (2H, d).

Synthesis of2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (28b)

4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (10.90 g,40.15 mmol) was dissolved in 100 mL dry EtOH and set to stir at roomtemperature. NaOH pellets (4.81 g, 120.45 mmol) were added in oneportion, and the reaction mixture was allowed to stir for 10 minutes.1-Bromo-2-methyl propane (5.0 g, 36.49 mmol) was then added, and thereaction mixture was allowed to stir at ambient temperature for 20hours. Upon completion (LCMS), the reaction mixture was diluted withwater and the pH was lowered to ˜pH2. The reaction mixture was thenwashed 3× with EtOAc. The organic phase was concentrated in vacuo andthen diluted with 200 mL aqueous MeOH. Oxone (10.02 g, 14.57 mmol) wasadded in one portion and the reaction was stirred at room temperaturefor 4 hours. Conversion of sulfide to sulfone was monitored via LCMS.Upon completion, reaction was quenched by the addition of sodiumthiosulfate. Salts were filtered, and the reaction mixture was washed 3×with ethyl acetate and dried over sodium sulfate. The organics wereevaporated by vacuum under reduced pressure. Product was purified viaHPLC. Yield: 1.1 g, 23.1%. m/z (LCMS) M⁺ 322.01, R_(f)=2.03. δ_(H) 12.6(1H, brs), 3.5 (4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.25 (2H, d), 3.0 (2H,m), 2.9 (2H, d), 2.4 (1H, m), 1.3 (6H, d d).

Synthesis of2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acid(28c)

4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (11.16 g,40.74 mmol) was dissolved in 100 mL dry EtOH and set to stir at roomtemperature. NaOH pellets (4.81 g, 120.25 mmol) were added in oneportion, and the reaction mixture was allowed to stir for 10 min.Bromomethylcyclopropane (5.0 g, 37.04 mmol) was then added, and thereaction mixture was allowed to stir at ambient temperature for 20hours. Upon completion (LCMS), the reaction mixture was diluted withwater and the pH was lowered to ˜pH2. The reaction mixture was thenwashed 3× with EtOAc. The organic phase was concentrated in vacuo andthen diluted with 200 mL aqueous MeOH. Oxone (15.6 g, 24.0 mmol) wasadded in one portion and the reaction was stirred at room temperaturefor 4 h. Conversion of sulfide to sulfone was monitored via LCMS. Uponcompletion, reaction was quenched by the addition of sodium thiosulfate.Salts were filtered, and the reaction mixture was washed 3× with ethylacetate and dried over sodium sulfate. The organics were evaporated byvacuum under reduced pressure. Product was purified via HPLC. Yield: 1.2g, 15.1%. m/z (LCMS) M⁺ 320.1, R_(f)=1.84. δ_(H) 12.6 (1H, br s), 3.5(4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.25 (2H, d), 3.0 (2H, m), 2.9 (2H,d), 2.4 (1H, m), 1.1 (1H, m), 0.62 (2H, q), 0.38 (2H, q).

Synthesis of2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (28d)

4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (1.27 g, 4.64mmol) was dissolved in 50 mL dry EtOH and set to stir at roomtemperature. NaOH pellets (556 mg, 13.92 mmol) were added in oneportion, and the reaction mixture was allowed to stir for 10 min.2-(Difluoromethoxy)-benzyl bromide (1.00 g, 4.219 mmol) was then added,and the reaction mixture was allowed to stir at ambient temperature for20 h. Upon completion (LCMS), the reaction mixture was diluted withwater and the pH was lowered to −2. The reaction mixture was then washed3× with EtOAc. The organic phase was concentrated in vacuo and thendiluted with 100 mL aqueous MeOH. Oxone (1.58 g, 2.43 mmol) was added inone portion and the reaction was stirred at room temperature for 4 h.Conversion of sulfide to sulfone was monitored via LCMS. Uponcompletion, reaction was quenched by the addition of sodium thiosulfate.Salts were filtered, and the reaction mixture was washed 3× with ethylacetate and dried over sodium sulfate. The organics were evaporated byvacuum under reduced pressure. Product was purified via HPLC. Yield: 195mg, 19.0%. m/z (LCMS) M⁺ 422.1. R_(f)=2.42. δ_(H) 12.6 (1H, br s),7.6-7.2 (4H, m), 7.19 (1H, s) 4.5 (2H, s), 3.5 (4H, m), 3.5 (1H, m), 3.4(4H, m), 3.2 (2H, d), 2.75 (2H, d).

Reference 29(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid (5a)(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid (5b)(R)-2-((S)-1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid (5c)(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-fluoro-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid (5d)

Compounds 5a, 5b, 5c and 5d were prepared according to the followingreaction protocol:

(S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (1a) &(S)-2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (1b)

Morpholine (14.48 ml) and Triethylamine (23.14 ml, 166 mmol) were addedto an ice-cold solution of acetic acid(S)-2,5-dioxo-tetrahydro-furan-3-yl ester (25 g, 158.12 mmol) in dry THF(600 ml) and the solution was stirred at room temperature over theweek-end. Solvent was evaporated under reduced pressure, residue dilutedwith water, acidified to pH 2 with 1N HCl and extracted with ethylacetate. Combined organic extracts were dried over MgSO₄ and evaporatedunder reduced pressure to give a mixtureof(S)-3-acetoxy-4-morpholin-4-yl-4-oxo-butyric acid and2-acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (14 g) as colorless oil.MS: 246 (MH⁺).

(S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (2a)

To a mixture of (S)-3-acetoxy-4-morpholin-4-yl-4-oxo-butyric acid and2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (11 g, 44.8 mmol) in drymethanol (30 ml) HCl in dioxane (4M, 7.3 ml, 29.16 mmol) was added andstirred at room temperature for 5 hrs. The reaction mixture wasneutralized with solid NaHCO₃, filtered through a mixture ofCelite/Na₂SO₄ (1:1) and concentrated under reduced pressure to give amixture of (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methylester and (S)-2-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methylester. Column chromatography on silica eluting with a mixture of ethylacetate and methylene chloride gave(S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester, (6 g) aswhite solid; ¹H NMR (CDCl₃) δ 2.62 (d, J=8 Hz, 2H), 3.78-3.44 (m, 11H),3.76 (d, J=9 Hz, 1H), 4.8-4.73 (m, 1H); MS: 218(MH⁺).

(E)-(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pent-4-enoicacid methyl ester (3a)

Lithium hexamethyldisilazide (1M in THF, 14.5 ml, 14.5 mmol) was addedto a solution of (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acidmethyl ester (1.5 g, 6.9 mmol) in dry THF (15 ml) at −78° C. under N₂and stirred for 30 min. Cinnamyl bromide (1.6 g, 7.32 mmol) was thenadded, the reaction mixture stirred at −78° C. for 2 hrs, warmed up toroom temperature and stirred overnight at room temperature. The reactionwas quenched with saturated ammonium chloride solution, adjusted the pHto 6 with 1N HCl and extracted with ethyl acetate. Combined ethylacetate extracts were dried over MgSO₄ and concentrated under reducedpressure to give pale brown solid. Column chromatography on silicaeluting with a mixture of ethyl acetate and methylene chloride gave thetitle compound as pale, yellow solid (1.15 g).

(E-(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pent-4-enoicacid methyl ester (3b)

Similarly prepared according to the procedure above but replacingcinnamyl bromide with1-((E)-3-Bromo-propenyl)-2-difluoromethoxy-benzene.

(2R,3S)-2-Benzyl-3-hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methylester (3c)

Similarly prepared according to the procedure above but replacingcinnamyl bromide with benzyl bromide.

(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid methyl ester (4a)

A solution of(E)-(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pent-4-enoicacid methyl ester (1.55 g, 4.65 mmol) in methanol (15 ml) washydrogenated at 50 psi over Pd/C for 4 hrs. The catalyst was removed byfiltration through celite and the filtrate concentrated under reducedpressure to give(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid methyl ester as pale, brown solid (1.45 g); ¹H NMR (CDCl₃) δ1.90-1.65 (m, 4H), 2.62-2.75 (m, 3H), 3.75-3.40 (m, 11H), 4.0 (d, J=15Hz, 1H), 4.47-4.4.39 (m, 1H), 7.38-7.15 (m, 5H); MS: 336(M⁺).

(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid methyl ester (4b)

Similarly prepared according to the procedure above but using(E)-(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pent-4-enoicacid methyl ester; ¹H NMR (CDCl₃) δ 1.93-1.58 (m, 4H), 2.78-2.58 (m,3H), 3.80-3.42 (m, 11H), 4.03 (m, 1H), 4.44 (m, 1H), 6.53 (t, J=74 Hz,1H), 7.25-7.04 (m, 4H); MS: 402(MH⁺).

(S)-2-((R)-1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid methyl ester (4c)

(Diethylamino) sulfur trifluoride (2.0 ml, 15.2 mmol) was added to a icecold solution of(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid methyl ester (4a) (0.85 g, 2.5 mmol) in dry methylene chloride (15ml) and the reaction mixture was stirred overnight while warming to roomtemperature. The reaction was quenched with aqueous NaHCO₃ solution andextracted with methylene chloride. The organic extracts were dried overNa2SO₄ and concentrated under reduced pressure. Column chromatography onsilica eluting with a mixture of ethyl acetate and methylene chloridegave the title compound as an off-white solid (230 mg). ¹H NMR (CDCl₃) δ1.90-1.58 (m, 4H), 2.78-2.57 (m, 2H), 3.28-3.10 (m, 1H), 3.75 (s, 3H),3.74-3.45 (m, 8H), 5.40-5.12 (m, 1H), 7.35-7.18 (m, 5H); MS: 338(MH⁺).

(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid (5a)

A solution of(R)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid methyl ester (230 mg, 0.69 mmol) and LiOH.H₂O (57.5 mg, 1.37 mmol)in a mixture of THF and water (2:1, 6 ml) was stirred at roomtemperature for 2.5 hrs. The reaction was diluted with water and THFremoved under reduced pressure. The pH of the aqueous solution wasadjusted to pH5 with 1N HCl and extracted with ethyl acetate. Thecombined organic extracts were dried over MgSO₄ and evaporated underreduced pressure to give the title compound as white solid (180 mg); ¹HNMR (CDCl₃) δ 1.92-1.60 (m, 4H), 2.75-2.60 (m, 3H), 3.78-3.45 (m, 9H),4.5 (d, J=8 Hz, 1H), 7.35-7.18 (m, 5H); MS: 322(MH⁺).

(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid (5b)

Similarly prepared according to the procedure above but using(R)-5-(2-difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid methyl ester; ¹H NMR (CDCl₃) δ 1.90-1.65 (m, 4H), 2.77-2.68 (m,3H), 3.70-3.53 (m, 9H), 4.51 (d, J=4.4 Hz, 1H), 6.52 (t, J=74 Hz, 1H),7.28-7.14 (m, 4H); MS: 388(M⁺).

(2R,3S)-2-Benzyl-3-hydroxy-4-morpholin-4-yl-4-oxo-butyric acid (5e)

Similarly prepared according to the general procedure above but using(2R,3S)-2-Benzyl-3-hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methylester; ¹H NMR (CDCl₃) δ 2.90 (m, 1H), 3.10 (m, 2H), 3.70-3.15 (m, 8H),3.75 (m, 1H), 4.32 (d J=7.5 Hz, 1H), 7.38-7.25 (m, 5H); MS: 294 (Mt).

Reference 30 2-Amino-1-benzooxazol-2-yl-butan-1-one

2-Amino-1-benzooxazol-2-yl-butan-1-one was prepared according to thefollowing reaction protocol:

[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butylester (1a)

DIPEA (0.35 ml, 2 mmol) and di-tert-butyl dicarbonate (355 mg, 1.63mmol) were added to a solution of 2-Amino-1-benzooxazol-2-yl-butan-1-ol(320 mg, 1.55 mmol) in dry methylene chloride (10 ml) and stirred atroom temperature for 4 hrs. The reaction was quenched with saturatedaqueous NH₄Cl and the pH was adjusted to neutral. Organic layerseparated and the aqueous layer extracted with methylene chloride. Thecombined organic extracts were dried over MgSO₄ and concentrated underreduced pressure to give,1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butylester (500 mg).

[1-(Benzooxazole-2-carbonyl)-propyl]-carbamic acid tert-butyl ester (2a)

Dess-Martin Periodinane (15% in DCM, 3.1 mmol) was added to a solutionof, 1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butylester in dry methylene chloride (15 ml) and stirred at room temperaturefor 4 hrs. A solution of Na₂S₂O₃ in aqueous NaHCO₃ was added and stirredat room temperature. Organic layer was separated and the aqueous wasextracted with methylene chloride. The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to give a palebrown solid. Column chromatography on silica eluting with a mixture ofmethylene chloride and heptane gave the title compound as off whitesolid (380 mg).

2-Amino-1-benzooxazol-2-yl-butan-1-one hydrochloride (3a)

Hydrogen chloride in dioxane (1M, 1 ml) was added to a solution of,1-(Benzooxazole-2-carbonyl)-propyl]-carbamic acid tert-butyl ester (2a)in dry methylene chloride (3 ml) and stirred at room temperature for 4hrs. Concentration under reduced pressure gave the title compound aswhite solid (65 mg); ¹H NMR (CDCl₃) δ 0.99 (t, J=7.5 Hz, 3H), 2.20-2.05(m, 2H), 4.96 (m, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H),7.94 (d, J=8.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.75 (m, 3H); MS:207(MH⁺).

(1-Amino-cyclopropyl)-oxazol-2-yl-methanone hydrochloride (3b)

¹H NMR (DMSO) δ 1.79 (m, 2H), 1.22 (m, 2H), 7.58 (s, 1H), 8.49 (s, 1H),9.22 (m, 3H); MS: 153(MH⁺).

Reference 31 2-Amino-1-oxazol-2-yl-butan-1-ol

2-Amino-1-oxazol-2-yl-butan-1-ol was prepared according to the followingreaction scheme:

Step 1

To a stirring solution of the BOC-L-x-aminobutyric acid (1, 17.75 g,87.3 mmol) in dry methylene chloride (35 ml) was added DIEA (33.45 ml)followed by the N,O-dimethylhydroxylamine hydrochloride (9.37 g, 96.03mmol) and PYBOP (50.0 g, 96.03 mmol). The reaction mixture was stirredovernight at room temperature. After the solvent was removed in vacuo,the oily residue was dissolved in ether and the precipitate which formedwas filtered and the filtrate was concentrated to give 35.0 g of a brownoil. The residue was dissolved in ethyl acetate and washed twice with0.05N HCl, saturated sodium bicarbonate and brine. The organic layer wasdried over magnesium sulfate and concentrated to give 14.0 g of theproduct 2, which was used without further purification.

Step 2

Compound 2 (8.4 g, 34.1 mmol) was then dissolved in 30 ml of dry THF andcooled to −50° C. under nitrogen, then LAH (1.0 M in THF, 37.5 ml, 37.51mmol) was added drop wise over 30 minutes. The reaction was stirred for1.5 hours at −50° C. then allowed to warn to 0° C. over 45 minutes. ThenNaHSO4 (6.12 g, 44.33 mmol) was added slowly followed by cold water (2.0ml) and stirring was continued for 30 minutes. The reaction was filteredthrough celite, which was washed with methylene chloride. The volatileswere removed from the filtrate in vacuo. The solid residue was dissolvedin ethyl acetate and washed with cold 0.05N HCl, water and brine. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated to give 6.5 grams of compound 3 as colorless oil.

Step 3

Triethylborane (1.0 M in THF, 149.5 ml, 149.5 mmol) was added to oxazole(10.33 g, 149.5 mmol) and stirred for 45 minutes at room temperature.The mixture was then cooled to −78° C. and n-BuLi (2.5 M in hexane, 59.8ml, 149.5 mmol) was added dropwise and allowed to stir for one hourunder nitrogen. Compound 3 (8.0 g, 42.7 mmol) was dissolved in 25 ml ofTHF and added to the reaction mixture. The reaction was stirred for 5hours at −78° C. then it was allowed to warm to 0° C. for one hour. Thereaction was then cooled back to −78° C. and quenched with 7% aceticacid in ethanol (700 ml) which was allowed to stir overnight at roomtemperature. The mixture was concentrated in vacuo and the residue wasdissolved in ether and filtered. The filtrate was concentrated in vacuoand the residue was dissolved in ethyl acetate washed twice with 0.005 NHCl, twice with sat'd sodium bicarbonate and brine. The organic layerwas dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified on silica using 10-40% ethyl acetate/heptane togive 3.85 grams of pure product 4.

Step 4

To a solution of compound 4 (1.1 g, 4.29 mmol) in dry methylene chloride(10.0 ml), stirring under nitrogen at room temperature, was added 4M HCl(in dioxane, 10.73 ml) dropwise followed by 5 ml of methanol. Thereaction was stirred overnight then concentrated in vacuo to give 1.2grams of compound 5 as a brown solid.

The following reference compounds were prepared according to theprotocol described in Reference 31:

2-Amino-3,3-dimethyl-1-oxazol-2-yl-butan-1-ol

2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol

LCMS retention time 1.10 minutes; M+1 (233.1)

Reference 32 2-Amino-2-methyl-pentan-1-ol

2-Amino-2-methyl-pentan-1-ol was prepared according to the followingreaction scheme:

Step 1

S-(+)-Phenylglycinol (1, 25 g, 182 mmol) was dissolved intrifluoroethanol (250 ml) and ethyl pyruvate (23.3 g, 200 mmol) wasadded (exothermic) followed by molecular seives (4 angstroms) and thereaction was refluxed overnight. The reaction was filtered andconcentrated to an oil. The oil was purified on a 500 g silica gelcolumn and eluted with 3:1 heptane/ethyl acetate to give 19.94 grams ofcompound 2.

Step 2

Compound 2 (15.0 g, 79 mmol) was dissolved in THF (400 ml) and cooled to−78° C., the boron trifluoride etherate (22.4 g, 158 mmol) was addedover a 15 minute period. The reaction was allowed to stir at −78 degreeC. for 2 hours and propyl magnesium chloride (2.0 M in ether, 79 ml, 158mmol) was added over a one hour period and allowed to stir for 4 hoursat −78° C. The reaction was allowed to warm to room temperature and stirovernight. The mixture was carefully quenched with sat'd NaHSO4 until pHof 8 was obtained. The reaction was extracted with ethyl acetate (2×200ml), then washed with water, brine, dried over sodium sulfate andconcentrated to dryness. The residue was purified on silica eluting with4:1 heptane/ethyl acetate to give 12.2 grams of compound 3.

Steps 3 and 4

Compound 3 (9.0 g, 39 mmol) was dissolved in ethanol (100 ml) and water(20 ml) followed by the addition of 9 grams of Pd(OH)₂ and TFA (4 ml).The mixture was hydrogenated at 50 psi for 48 hours, then the reactionwas filtered through celite which was concentrated to give 9 grams ofcrude material 4 which was used without further purification. Compound 4was dissolved in dry methanol (300 ml) and HCl gas was bubbled throughfor 15 minutes. The reaction was stirred at room temperature for threedays and was concentrated. The crude product was purified on silicaeluting With 1:1 heptane/ethyl acetate to give 3.9 grams of compound 5.

Step 5

A mixture of compound 5 (3.9 g, 27 mmol), (BOC)2O (5.88 g, 27 mmol), andTEA (7.56 ml, 54 mmol) in 100 ml of dioxane and 100 ml of water werestirred overnight at room temperature. The reaction mixture wasconcentrated and dissolved in ethyl acetate and washed with brine. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude product was purified on silica elutingwith 30 ethyl acetate/heptane to give 6.68 gram of pure product 6.

Step 6

A solution of compound 6 (6.68 g, 27 mmol) in 200 ml of THF was cooledto 0° C. and LAH (1.0M in THF, 32.4 ml, 32.4 mmol) was added dropwiseand the reaction was stirred for 30 minutes then allowed to come to roomtemperature. The reaction was stirred for another 30 minutes and thereaction was quenched with a solution of NaHS04, the THF was removed invacuo and the residue was extracted with ethyl acetate which was washedwith brine and concentrated. The product was purified on silica elutingwith n-heptane to 5% methanol/ethyl acetate to give 2.8767 g of compound7.

Step 7

Compound 7 (0.5 g) was dissolved in 5 ml of 4N HCL in dioxane andstirred for 1 hour at room temperature. The reaction was concentratedand dried under high vacuum to give 0.3859 g of compound 8, which wasused without further purification.

The following reference compounds were prepared according to theprotocol described in Reference 32:

2-Amino-2-methyl-4-phenyl-butan-1-ol

2-Amino-2-methyl-butan-1-ol

Reference 33 2-Amino-2-methyl-1-oxazol-2-yl-pentan-1-one

2-Amino-2-methyl-1-oxazol-2-yl-pentan-1-one was prepared according tothe following reaction scheme:

Step 1

A solution of oxalyl chloride (2.0M in CH₂Cl₂, 1.5 ml, 3 mmol) in 5 mlof methylene chloride was cooled to −78° C., then DMSO (0.44 ml) wasadded drop wise to the mixture and allowed to stir for 5 minutes. Asolution of compound 7 (Scheme 2, 0.4346 g, 2.0 mmol) in 10 ml ofmethylene chloride was added drop wise. The reaction was stirred at −78degree C. for 15 minutes and TEA (1.12 ml, 8 mmol) was added dropwiseand the reaction was stirred for 2 hours at room temperature. Thereaction was quenched with water and the product was extracted withethyl acetate, then organic layer was washed with brine and the solventwas removed in vacuo. The crude product was purified on silica elutingwith heptane to 10% ethyl acetate/heptane to give 0.3131 g of purecompound 9.

Step 2

Triethylborane (1.0 M in THF, 4.84 ml, 4.84 mmol) was added to oxazole(0.3355 g, 4.84 mmol) in 4 ml of THF and stirred for 30 minutes at roomtemperature. The mixture was then cooled to −78° C. and n-BuLi (1.6 M inhexane, 3.025 ml, 4.84 mmol) was added dropwise and allowed to stir forone hour under nitrogen. Compound 9 (0.2615 g, 1.21 mmol) was dissolvedin 5 ml of THF and added to the reaction mixture. The reaction wasstirred for 5 hours at −78° C., then quenched with 5% acetic acid inethanol (20 ml) which was allowed to stir overnight at room temperatureand concentrated in vacuo. Ether was added and the solid was filteredand the filtrate was concentrated and the crude product was purified onsilica using 0-20% ethyl acetate/heptane to give 0.2528 grams of pureproduct 10.

Step 3

Dess-Martin periodinane (15% in CH2Cl2, 4.95 g, 1.8 mmol) was added to astirring added to a stirring solution of compound 10 (0.2528 g, 0.89mmol) in 5 ml of methylene chloride. The reaction was stirred at roomtemperature for 3 hours, then the reaction was quenched with a solutionof sodium thiosulfate in sat'd sodium bicarbonate. The product wasextracted with ethyl acetate and the organic layer was washed withbrine, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified on silica eluting with 1:1 ethyl acetate/heptane to5% methanol/ethyl acetate to give 0.2307 g of pure compound 11.

Step 4

Compound 11 (0.2123 g, 0.75 mmol) was dissolved in 5 ml of 4N HCL indioxane and stirred for 1 hour at room temperature. The reaction wasconcentrated and dried under high vacuum to give 0.1713 g of compound 8,which was used without further purification.

The following reference compounds were prepared according to theprotocol described in Reference 33:

2-Amino-1-benzooxazol-2-yl-2-methyl-pentan-1-one

LCMS retention time 2.45 minutes; M+1 (233.1).

2-Amino-1-benzooxazol-2-yl-2-methyl-4-phenyl-butan-1-one

LCMS retention time 2.79 minutes; M+1 (295.1)

2-Amino-1-benzooxazol-2-yl-2-methyl-butan-1-one

LCMS retention time 2.29 minutes; M+1 (219.1)

2-Amino-2-methyl-1-oxazol-2-yl-propan-1-one

LCMS retention time 1.63 minutes; M+1 (155.1)

Reference 34 2-Amino-4-phenyl-butyramide

2-Amino-4-phenyl-butyramide was prepared according to the followingreaction scheme:

Step 1

Compound 1 (5 g, 15.5 mmol) was dissolved in dry ether (150 ml) andcooled to −20° C., then perfluoroethyl iodide (25 g, 100 mmol) wasbubbled into the mixture. The solution was then cooled to −50° C. andmethyl lithium/lithium bromide complex was added over a 30 minuteperiod. The reaction was stirred for 1.5 hours at this temperature andwas then quenched with acetone. After stirring for 15 minutes thereaction was diluted with ether (100 ml) and poured onto 100 ml of watercontain KHSO4. The organic layer was separated and washed with water,brine, dried over sodium sulfate and concentrated to dryness. Thematerial was purified on silica eluting with 1:1 ethyl acetate/heptaneto give 1.7 grams of compound 2.

Step 2

Compound 2 (0.35 g) was dissolved in 4 ml of 4N HCL in dioxane andstirred for 1 hour at room temperature. The reaction was concentratedand dried under high vacuum to give 0.2807 g of compound 3 which wasused without further purification; LCMS retention time 4.19 minutes; M+1(282.1).

Example 1N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide

A mixture comprised of 3-benzylsulfanyl-2-benzylsulfanylmethyl-propionicacid (0.239 g, 0.719 mmol), prepared as in Reference 1, in methylenechloride (6 mL), HOBt hydrate (0.11 g, 0.719 mmol), EDC (0.18 g, 0.939mmol), hydroxy amine (0.19 g, 0.86 mmol) and 4-methylmorpholine (0.075mL) was stirred at room temperature for 1 hour and then poured into cold1N aqueous hydrochloric. The product was extracted with ethyl acetateand the extracts were washed with saturated aqueous sodium chloride andthen dried over magnesium sulfate. The solvent was removed by rotaryevaporation at reduced pressure and the residue was chromatographed onsilica gel eluting with ethyl acetate/hexane to giveN—[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide(0.217 g).

A solution ofN—[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide(0.317 g, 0.594 mmol) in methanol (30 mL) was treated with a solution ofOxone® (0.913 g, 1.48 mmol) in water (20 mL) and then stirred at roomtemperature for 7 hours. The methanol was removed by evaporation atreduced pressure and the resulting suspension was diluted with water andthe product extracted with ethyl acetate. The extracts were washed withsaturated aqueous sodium chloride and then dried over magnesium sulfate.The solvent was removed by rotary evaporation at reduced pressure andthe residue was chromatographed on silica gel eluting with ethylacetate/hexane to giveN—[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide(0.143 g, 41% yield).

A solution ofN—[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide(0.140 g, 0.234 mmol) in methylene chloride (5 mL) was treated with1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (0.127 g, 0.30 mmoL) and the resulting solution was stirredat room temperature for 30 minutes. Aqueous sodium thiosulfate andsodium bicarbonate (15 mL, 0.25 M) were added and the reaction mixturewas stirred for 20 minutes. The product was extracted with ethylacetate. The extracts were washed with saturated aqueous sodium chlorideand then dried over magnesium sulfate. The solvent was removed by rotaryevaporation at reduced pressure and the residue was crystallized fromt-butylmethyl ether to giveN—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzyl-sulfonylmethyl-propionamide(0.103 g, 74%); NMR (DMSO): 9.15 (d, J=6 Hz, 1H); 8.01 (d, J=7 Hz, 1H);7.89 (d, J=8 Hz, 1H); 7.65 (t, J=7 Hz, 1H); 7.54 (t, J=8 Hz, 1H); 7.37(m, 10H); 5.36 (m, 1H); 4.5 (m, 4H); 3.68 (m, 1H); 3.45-3.25 (m, 4H);1.95 (m, 1H); 1.73 (m, 1H); 1.47 (m, 2H); 0.91 (t, J=7 Hz, 3H); MS:M(H+) 597.0 (596.17);

The following compounds were prepared by the method of Example 1 bysubstituting the required carboxylic acid in place of3-benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid:

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide(Compound 2); ¹H-NMR (CDCl₃) δ: 7.93 (m, 1H); 7.69 (m, 4H); 7.4-7.6 (m,6H); 7.20 (m, 2H); 5.58 (m, 1H); 4.54 (m, 4H); 3.69 (m, 1H); 3.30-3.55(m, 4H); 1.55-1.90 (m, 1H); 1.45 (m, 1H); 1.32 (m, 2H); 0.90 (m, 3H);MS: M(+) 733.0; M(−) 731.6;

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-(2-methoxy-benzenesulfonyl)-2-[2-(2-methoxy-benzenesulfonyl)-ethyl]-butyramide(Compound 3); ¹H-NMR (DMSO) δ: 8.65 (d, 1H); 7.99 (d, J=7 Hz, 1H); 7.89(d, J=8 Hz, 1H); 7.8-7.5 (m, 6H); 7.3-7.1 (m, 4H); 5.25 (m, 1H); 3.90(m, 9H); 3.3 (m, 6H); 1.6 (m, 4H); 1.3 (m, 2H); 0.85 (m, 3H); MS: (M+)670.2, 670.19;

4-Benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-butyramide(Compound 4); ¹H-NMR (DMSO) δ: 8.61 (d, J=6 Hz, 1H); 7.99 (d, J=8 Hz,1H); 7.91 (d, J=8 Hz, 1H); 7.82 (m, 4H); 7.74 (m, 2H); 7.64 (m, 5H);7.55 (t, J=8 Hz, 1H); 5.21 (m, 1H); 3.3-3.0 (m, 5H); 1.8 (m, 1H); 1.6(m, 5H); 1.3 (m, 2H); 0.86 (t, J=7 Hz, 3H); MS: (M+) 597.2, 596.17;

(Z)-N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-2-cyclohexylmethyl-3-benzylsulfonyl-propionamide(Compound 5); ¹H NMR (DMSO): 8.96 (d, J=6 Hz, 1H), 8.73 (d, J=6 Hz, 1H),7.99 (d, J=8H, 1H), 7.87 (m, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.37 (m,5H), 5.29 (m, 1H), 4.44 (s, 2H), 4.36 (s, 2H), 3.3-2.8 (m, 2H), 0.6-2.0(m, 20H); MS: MH⁺ 525.4 (524.23); and

N—[(S)-1-(1-Benzothiazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide(Compound 6); ¹H NMR: (DMSO), 8.79 (d, J=6.2 Hz), 8.72 (d, J=6.2 Hz),1H], 8.30-8.22 (m, 2H), 7.71-7.61 (m, 2H), 7.43-7.33 (m, 5H), 5.46-5.33(m, 1H), 4.53-4.38 (m, 2H), 3.57-3.30 (m, 10H), 3.13-3.02 (m, 1H),2.66-2.54 (m, 2H), 2.04-1.90 (m, 1H), 1.83-1.68 (m, 1H), 0.97 (t, J=7.2Hz, 3H); MS: (M⁺+1) 558.

The method of Example 1 can also be modified by omitting the Oxone®oxidation step to prepare the following compounds:

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-cyclohexyl-2-cyclohexylmethyl-propionamide(Compound 7); ¹H NMR (DMSO): 8.50 (d, J=6 Hz, 1H); 8.00 (d, J=8 Hz, 1H);7.89 (d, J=8 Hz, 1H); 7.62 (t, J=7 Hz, 1H); 7.53 (t, J=7 Hz, 1H); 5.2(m,1H); 2.0-0.8 (m, 35H); MS: M(H+) 453.2 (452.3);

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide(Compound 8); ¹H NMR (DMSO): 8.73 (d, J=5 Hz, 1H); 7.76 (d, J=7 Hz, 1H);7.87 (d, J=8 Hz, 1H); 7.62 (dt, J=7.1 Hz, 1H); 7.52 (dt, J=8.1 Hz, 1H);5.26 (m, 1H); 2.7 (m, 1H); 2.55 (m, 4H); 2.34 (d, J=7 Hz, 2H); 2.29 (d,J=7 Hz, 2H); 1.9 (m, 1H); 1.66 (m, 3H); 1.45 (m, 2H); 0.91 (t, J=6 Hz,3H), 0.90 (d, J=6 Hz, 6H), 0.88 (d, J=3 Hz, 3H), 0.84 (d, J=3 Hz, 3H);MS: M(H+) 465.0 (464.22);

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide(Compound 9); ¹H NMR (DMSO): 8.80 (d, J=7 Hz, 1H); 7.98 (d, J=8 Hz, 1H);7.88 (d, J=8 Hz, 1H); 7.63 (t, J=7 Hz, 1H); 7.53 (t, J=7 Hz, 1H);7.3-7.2 (m, 10H); 5.32 (m, 1H); 3.71 (s, 2H); 3.65 (d, J=3 Hz, 2H); 2.87(m, 1H); 2.45-2.3 (m, 4H); 2.0-1.4 (m, 4H); 0.92 (t, J=7 Hz, 3H); MS:M(H+) 533.0 (532.19); and

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide(Compound 10); ¹H NMR (DMSO): 8.73 (d, J=6 Hz, 1H); 7.99 (d, J=8 Hz,1H); 7.88 (d, J=8 Hz, 1H); 7.65 (t, J=8 Hz, 1H); 7.53 (t, J=8 Hz, 1H);7.35-7.1 (m, 10H); 5.3 (m, 1H); 2.85 (m, 4H); 2.65 (m, 1H); 2.0-1.3 (m,8H); 0.91 (t, J=7 Hz, 3H); MS: M(H+) 533.0 (532.19).

Example 2N-Cyanomethyl-4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzyl-sulfonylmethyl)-butyramide

A mixture comprised of4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyricacid (200 mg, 0.47 mmol), prepared as in reference 5, EDC (200 mg, 1.05mmol), HOBt (200 mg, 1.3 mmol), and aminoacetonitrile hydrochloride (150mg, 1.6 mmol) was treated with dichloromethyl (4 mL) and4-methylmorpholine (0.5 mL). The mixture was stirred at ambienttemperature for 2 hours. After dilution with ethyl acetate (150 mL), thesolution was washed with water (30 mL), saturated aqueous NaHCO₃solution and brine, dried with magnesium sulfate and evaporated undervacuum. The product was crystallized from ethyl acetate/hexane to yieldN-cyanomethyl-4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzyl-sulfonylmethyl)-butyramide(156 mg) as a yellowish solid; ¹H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H),7.81-7.57 (m, 4H), 4.74 (d, J=14.5 Hz, 1H), 4.67 (d, J=14.5 Hz, 1H),4.13 (d, J=5.5 Hz, 2H), 3.63-3.26 (m, 11H), 2.75 (dd, J=6.4 Hz, J=16.8Hz, 1H), 2.65 (dd, J=6.2 Hz, J=16.8 Hz, 1H); MS: (M⁺+1) 462;

The following compounds of Formula I were provided by proceeding as inExample 2:

N⁴-(4-Carbamoyl-phenyl)-N¹-cyanomethyl-2-benzyl-sulfonylmethyl-succinamide(Compound 19); ¹H NMR: (DMSO) 10.24 (s, 1H), 8.93 (t, J=5.5 Hz, 1H),7.83 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.44-7.35(m, 5H), 7.23 (s, 1H), 4.53 (d, J=13.6 Hz, 1H), 4.48 (d, J=13.6 Hz, 1H),4.14 (m, 2H), 3.50-3.30 (m, 2H), 3.20 (dd, J=4.7 Hz, J=13.1 Hz, 1H),2.73 (d, J=6.7 Hz, 2H); MS: (M⁺+1) 443; and

N-Cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-4-morpholin-4-yl-4-oxo-butyramide(Compound 25); ¹H NMR: (DMSO) 8.85 (t, J=5.5 Hz, 1H), 7.52-7.43 (m, 2H),7.31-7.22 (m, 2H), 7.13 (t, J_(H,F)=74 Hz, 1H), 4.53 (s, 2H), 4.11 (d,J=5.5 Hz, 2H), 3.58-3.20 (m, 11H), 2.72 (dd, J=6.7 Hz, J=16.8 Hz, 1H),2.63 (dd, J=5.9 Hz, J=16.8 Hz, 1H); MS: (M⁺+1) 460;

Example 3N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

A mixture comprised of4-Morpholin-4-yl-4-oxo-2-(benzyl-sulfonylmethyl)-butyric acid (300 mg,0.84 mmol), EDC (250 mg, 1.3 mmol), HOBt (250 mg, 1.6 mmol) and(2S)-2-amino-1-benzooxazol-2-yl-butan-1-ol (250 mg, 1.2 mmol) wastreated with dichloromethyl (4 mL) followed by 4-methylmorpholine (0.5mL). The mixture was stirred at ambient temperature for 2 hours. Afterdilution with ethyl acetate (150 mL), the solution was washed with 1Naqueous HCl, water, saturated aqueous NaHCO₃ solution and brine, driedwith magnesium sulfate and evaporated under vacuum. The crude productwas dissolved in dry dichloromethyl (10 mL) and1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (500 mg, 1.2 mmol) was added. After stirring at ambienttemperature for 1 hour, the mixture was diluted with ethyl acetate (150mL) and treated with 0.26M Na₂S₂O₃ solution in saturated aqueous NaHCO₃.The organic phase was washed with saturated aqueous NaHCO3 and brine,dried with magnesium sulfate and evaporated to yieldN—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-propyl-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide(377 mg) as mixture of diastereomers. The product was purified by flashchromatography on silica gel (hexane/ethyl acetate ratio of 1:2 to 1:4);¹H NMR: (DMSO), 8.85 (d, J=6.2 Hz), 8.77 (d, J=6.2 Hz), 1H], 8.00 (d,J=7.7 Hz), 7.99 (d, J=7.7 Hz), 1H], 7.90 (d, J=8.2 Hz), 7.89 (d, J=8.2Hz), 1H], 7.64 (t, J=7.9 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.42-7.34 (m,5H), 5.25-5.12 (m, 1H), 4.55-4.38 (m, 2H), 3.60-3.28 (m, 10H), 3.12-3.02(m, 1H), 2.64-2.50 (m, 2H), 2.08-1.91 (m, 1H), 1.82-1.65 (m, 1H), 0.98(t, J=7.4 Hz, 3H); MS: (M⁺+1) 542;

The following compounds of Formula I were provided by proceeding as inExample 3:

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide(Compound 30); ¹H NMR: (DMSO), 8.84 (d, J=6.4 Hz), 8.76 (d, J=6.4 Hz),1H], 8.00 (d, J=7.7 Hz), 7.98 (d, J=7.7 Hz), 1H], 7.89 (d, J=8.2 Hz),7.88 (d, J=8.2 Hz), 1H], 7.64 (t, J=7.9 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H),7.42-7.34 (m, 5H), 5.30-5.17 (m, 1H), 4.53-4.37 (m, 2H), 3.56-3.26 (m,10H), 3.12-3.00 (m, 1H), 2.66-2.52 (m, 2H), 2.00-1.86 (m, 1H), 1.76-1.61(m, 1H), 1.48-1.22 (m, 4H), 0.85 (t, J=6.9 Hz, 3H); MS: (M⁺+1) 570;

(S)-2,2-Difluoro-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-3-oxo-hexanoicacid dimethylamide (Compound 31); ¹H NMR: (DMSO) 8.63-8.57 (m, 1H),7.43-7.34 (m, 5H), 4.69-4.57 (m, 1H), 4.55-4.41 (m, 2H), 3.59-3.30 (m,10H), 3.14-3.04 (m, 1H), 2.98 (s), 2.96 (s), 3H], 2.90 (s), 2.88 (s),3H], 2.70-2.58 (m, 2H), 1.90-1.72 (m, 1H), 1.66-1.50 (m, 1H), 0.89 (t,J=6.9 Hz, 3H); MS: (M⁺+1) 546; and

N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide(Compound 32); ¹H NMR: (DMSO) 9.26-9.19 (m, 1H), 8.56 (d, J=6.7 Hz),8.51 (d, J=6.9 Hz), 1H], 7.44-7.19 (m, 10H), 4.96-4.85 (m, 1H),4.53-4.40 (m, 2H), 4.38-4.22 (m, 2H), 3.57-3.30 (m, 10H), 3.11-2.99 (m,1H), 2.65-2.52 (m, 2H), 1.86-1.71 (m, 1H), 1.61-1.48 (m, 1H), 0.89 (t,J=7.2 Hz, 3H); MS: (M⁺+1) 558.

Example 53-Biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide

3-Biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (300 mg, 0.76mmol), prepared as in Reference 9, was combined with EDC (300 mg, 1.57mmol), HOBt (300 mg, 1.96 mmol), and aminoacetonitrile hydrochloride(150 mg, 1.6 mmol). Dichloromethyl (4 mL) was added and then4-methylmorpholine (0.5 mL). The mixture was stirred at ambienttemperature for 2 hours. After dilution with ethyl acetate (150 mL), thesolution was washed with water (30 mL), saturated aqueous NaHCO₃solution and brine, dried with magnesium sulfate and evaporated undervacuum. The product,3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide (273mg), was crystallized from ethyl acetate/hexane as a white solid; ¹HNMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.68-7.14 (m, 14H), 4.45 (d, J=13.8Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.13 (m, 2H), 3.49 (dd, J=9.4 Hz,J=14.1 Hz, 1H), 3.28-3.11 (m, 1H), 3.04-2.76 (m, 3H). MS: (M⁺+1) 433.

Proceeding as in Example 5 provided the following compound of Formula I:

3-Biphenyl-4-yl-N-cyanomethyl-2-benyzlsulfonylmethyl-propionamide(Compound 36); ¹H NMR: (DMSO) 8.86 (t, J=5.5 Hz, 1H), 7.65 (d, J=7.4 Hz,2H), 7.59 (d, J=7.4 Hz, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.39-7.24 (m, 8H),4.47 (d, J=13.8 Hz, 1H), 4.40 (d, J=13.8 Hz, 1H), 4.13 (m, 2H), 3.48(dd, J=9.4 Hz, J=14.1 Hz, 1H), 3.23-3.11 (m, 1H), 3.04-2.75 (m, 3H). MS:(M⁺+1) 433; and

3-(3-Bromo-phenyl)-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide(Compound 37); ¹H NMR: (DMSO) 8.84 (t, J=5.5 Hz, 1H), 7.46-7.14 (m, 9H),4.46 (d, J=13.8 Hz, 1H), 4.40 (d, J=13.8 Hz, 1H), 4.10 (m, 2H), 3.46(dd, J=9.4 Hz, J=14.1 Hz, 1H), 3.18-3.07 (m, 1H), 2.97 (dd, J=14.1 Hz,J=3.4 Hz, 1H) 2.88-2.73 (m, 2H). MS: (M⁺+1) 435/437.

Example 6N—[(S)-1-((E)-2-Benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide

A mixture of 3-benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid (161mg), prepared as in Reference 1,3-benzenesulfonyl-1-n-butylallylaminetosylate (212 mg), HOBt monohydrate (77 mg) and EDC (125 mg) inmethylene chloride (6 mL) was treated with N-methylmorpholine (0.25 mL)and stirred at room temperature for 2.5 hours. The reaction mixture waspoured into ice cold dilute hydrochloric acid. The product was extractedwith ethyl acetate and the organic extracts were washed with aqueoussodium bicarbonate and then with saturated sodium chloride. After dryingover magnesium sulfate the solvents were evaporated to give a residuewhich was crystallized from ethyl acetate/t-butylmethyl ether to yieldN—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide(160 mg).

A solution ofN—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide(50 mg) in methylene chloride (5 mL) was treated with m-chloroperbenzoicacid (108 mg) and then stirred at room temperature for 65 minutes. Thereaction mixture was stirred with aqueous sodium bisulfite and sodiumbicarbonate for 85 minutes and then extracted with methylene chloride.The organic extracts were washed with saturated aqueous sodium chlorideand dried over magnesium sulfate. Evaporation of the solvent gave aresidue which was precipitated from ethyl acetate/t-butylmethyl ether togiveN—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide(37 mg); ¹H NMR (DMSO): 8.61 (d, J=8 Hz, 1H), 7.80 (d, J=7 Hz, 2H), 7.69(t, J=7H, 1H), 7.58 (t, J=8 Hz, 2H), 7.38 (m, 10H), 6.86 (m, 2H),4.6-4.3 (m, 5H), 3.5-3.4 (m, 5H), 1.5 (m, 2H), 1.2 (m, 4H), 0.8 (m, 3H);MS: MH⁺ 632.2 (631.17).

Proceeding as in Example 6 provided the following compound of Formula I:

N-(3-Benzenesulfonyl-1-phenethyl-allyl-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide(Compound 39); ¹H NMR (DMSO): 8.75 (d, J=8 Hz, 1H), 7.80 (d, J=7 Hz,2H), 7.70 (t, J=7H, 1H), 7.58 (t, J=8 Hz, 2H), 7.4-7.1 (m, 15H), 6.9 (m,2H), 4.6-4.2 (m, 5H), 3.6-3.3 (m, 5H), 2.6 (m, 2H), 1.8 (m, 2H); MS: MH⁺680.4 (679.17);

Example 7N-Cyanomethyl-3-(3-cyano-benzylsulfonyl)-2-benzylsulfonyl-methylpropionamide

A mixture of 3-acetylsulfanyl-2-benzylsulfanylmethyl-propionic acid(0.200 g), prepared as in Reference 10, HOBt hydrate (0.13 g),aminoacetonitrile hydrochloride (0.15 g) and EDC (0.26 g) was treatedwith methylene chloride (6 mL) and N-methylmorpholine (0.35 mL). Afterstirring for 80 minutes at room temperature, the reaction mixture wasdiluted with ethyl acetate (50 mL) and washed sequentially with water,aqueous sodium bicarbonate and saturated aqueous sodium chloride. Thesolution was dried over magnesium sulfate and evaporated to givethioacetic acid S-[3-benzylsulfanyl-2-(cyanomethyl-carbamoyl)-propyl]ester (0.218 g).

A solution of thioacetic acidS-[3-benzylsulfanyl-2-(cyanomethyl-carbamoyl)-propyl]ester (0.105 g) indimethylformamide (1 mL) and water (0.8 mL) was cooled on ice andtreated with 1 N aqueous potassium hydroxide (0.65 mL).3-Cyanobenzylbromide (0.129 g) in dimethylformamide (0.8 mL) was added.The reaction mixture was allowed to warm to room temperature whilestirring overnight. The reaction mixture was then poured into ice waterand extracted with ethyl acetate (50 mL) and washed with water andsaturated aqueous sodium chloride. The solution was dried over magnesiumsulfate and evaporated to give2-benzylsulfanylmethyl-3-(3-cyano-benzylsulfanyl)-N-cyanomethyl-propionamide(0.135 g).

2-Benzylsulfanylmethyl-3-(3-cyano-benzylsulfanyl)-N-cyanomethyl-propionamide(0.135 mg) in methanol (10 mL) was treated with a solution of Oxone®(0.615 g) in water (1.3 mL) and the resulting mixture was stirred atroom temperature for 45 minutes. The reaction mixture was diluted withwater (50 mL) and then the methanol was removed by rotary evaporation.The residue was diluted with ethyl acetate and water. The product wasextracted with ethyl acetate and the organic layer washed with water andsaturated aqueous sodium chloride. The solution was dried over magnesiumsulfate and evaporated to giveN-Cyanomethyl-3-(3-cyano-benzylsulfonyl)-2-benzylsulfonylmethyl-propionamide(0.138 g); ¹H NMR: (DMSO) 9.19 (t, J=5 Hz, 1H), 7.88 (d, J=8 Hz, 1H),7.82 (s, 1H), 7.72 (d, J=9 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.38 (s, 5H),4.65 (d, J=14 Hz, 1H), 4.58 (d, J=14 Hz, 1H), 4.53 (d, J=13 Hz, 1H),4.47 (d, J=13 Hz, 1H), 4.17 (d, J=5 Hz, 2H), 3.5-3.3 (m, 5H); MS: (M⁺+1)460.2; 459.09.

Example 84-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide

A mixture of (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-one,prepared as in Reference 11,4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (200 mg, 0.56mmol), EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.30 mmol), CH₂Cl₂ (4 mL)and 4-methylmorpholine (0.5mL) was stirred at ambient temperature for 2hours. After dilution with ethyl acetate (150 mL), the solution waswashed with water (30 mL), saturated aqueous NaHCO₃ solution and brine,dried with MgSO₄ and evaporated under vacuum. The crude product wasdissolved in dry dichloromethyl (10 mL) and1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (500 mg, 1.2 mmol) was added. After stirring at ambienttemperatures for 1 hour, the mixture was diluted with ethyl acetate (150mL) and treated with Na₂S₂O₃ solution (0.26M) in saturated aqueousNaHCO₃. The organic phase was washed with saturated aqueous NaHCO₃ andbrine, dried with MgSO₄ and evaporated. The product was purified byflash chromatography on silica gel (hexane/ethyl acetate in a 1:2 to 1:4ratio) to yield4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl-propyl}-butyramide(150 mg) as mixture of diastereomers; ¹H NMR: (DMSO), 9.03 (d, J=5.9Hz), 8.89 (d, J=6.4 Hz), 1H], 8.09-8.03 (m, 2H), 7.66-7.55 (m, 3H),7.42-7.33 (m, 5H), 4.97-4.78 (m, 1H), 4.53-4.35 (m, 2H), 3.58-3.02 (m,11H), 2.65-2.50 (m, 2H), 2.06-1.90 (m, 1H), 1.83-1.66 (m, 1H), 0.97 (t,J=7.2 Hz, 3H); MS: (M⁺+1) 569.

Example 9N-Cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfanylmethyl]-3-benzylsulfanyl-propionamide

A mixture of2-benzylsulfanylmethyl-3-[2-(1,1-difluoromethoxy)-benzyl-sulfanyl]-propionicacid (96 mg, 0.241 mmol)(prepared above in Reference 2), HOBt hydrate(37 mg, 0.24 mmol), aminoacetonitrile hydrochloride (33 mg, 0.36 mmol),EDC (69 mg, 0.36 mmol) and N-methylpyrolidinone (1 mL) was treated withN-methylmorpholine (0.050 mL) and then stirred at room temperature for 3hours. The reaction mixture was then poured into cold dilute HCl and theproduct extracted with ethyl acetate, The organic extracts were washedwith aqueous sodium bicarbonate then saturated sodium chloride and driedover magnesium sulfate. Evaporation of the solvent then gaveN-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfanylmethyl]-3-benzylsulfanyl-propionamide(46 mg).

The following compounds of Formula I are provided by this method bysubstitution of2-benzylsulfanylmethyl-3-[2-(1,1-difluoromethoxy)-benzylsulfanyl]-propionicacid with the appropriate carboxylic acid:

N-Cyanomethyl-3-(2-trifluoromethyl-benzylsulfanyl)-2-(2-trifluoro-methyl-benzylsulfanylmethyl)-propionamide(Compound 43); ¹H-NMR (CDCl₃) δ: 7.57 (m, 6H); 7.36 (t, J=7.4 Hz, 2H);6.01 (m, 1H); 4.16 (d, J=5.9 Hz, 2H); 3.86 (s, 4H); 2.70 (m, 4H); 3.35(m, 1H); MS: (M+) 507.0, M(−) 504.2;

N-Cyanomethyl-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide(Compound 44); ¹H NMR (DMSO): 8.77 (t, J=6 Hz, 1H), 4.5 (d, J=6 Hz, 2H),2.60 (s, 5H), 2.34 (d, J=7 Hz, 4H), 1.70 (hept, J=7 Hz, 2H), 0.91 (d,J=7 Hz, 12H); MS: M(H+) 303.0 (302.15);

N-Cyanomethyl-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide(Compound 45); ¹H NMR (DMSO): 8.83 (t, J=5 Hz, 1H); 7.3 (m, 10H); 4.22(d, J=6 Hz, 2H); 2.90 (m, 4H); 2.65 (m, 1H); 1.85 (m, 2H); 1.72 (m, 2H);MS: M(H+) 370.4 (370.12);

N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfanylmethyl]-propionamide(Compound 46); ¹H NMR (DMSO): 8.88 (t, J=5 Hz, 1H); 7.4-7.1 (m, 8H);7.15 (t, J=74 Hz, 2H); 4.18 (t, J=3 Hz, 2H); 3.74 (d, J=13 Hz, 4H); 2.75(m, 1H); 2.65-2.5 (m, 4H); MS: M(H+) 504.1 (502.1); and

3-Benzylsulfanyl-2-benzylsulfanylmethyl-N-cyanomethyl-propionamide(Compound 47); ¹H NMR (DMSO): 8.86 (t, J=6 Hz, 1H); 7.26 (m, 10H); 4.20(d, J=5 Hz, 2H); 3.7 (s, 4H); 2.73 (m, 1H); 2.55-2.37 (m, 4H); MS: M(H+)370.4 (370.12).

Example 10N-Cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide

A solution ofN-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzyl-sulfanylmethyl]-3-benzylsulfanyl-propionamide(46 mg) in methanol (5 mL) was treated with Oxone® (184 mg in 2.5 mL ofwater) and stirred at ambient temperature for 18 hours. An additionalportion of Oxone® (166 mg in 1.5 mL of water) was added along with moremethanol (10 mL) and the reaction mixture was stirred again for 18hours. Water was added to the reaction mixture and the methanol wasremoved by rotary evaporation and the product was extracted with ethylacetate. The organic extracts were washed with aqueous sodiumbicarbonate then saturated sodium chloride and dried over magnesiumsulfate. Evaporation of the solvent then gaveN-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-phenyl-methylsulfonyl-propionamide(67 mg); ¹H NMR (DMSO): 9.19 (t, J=5 Hz, 1H), 7.47 (m, 2H), 7.38 (s,5H), 7.25 (m, 2H), 7.13 (t, J=74 Hz, 1H), 4.54 (s, 2H), 4.53 (d, J=14Hz, 1H), 4.46 (d, J=14 Hz, 1H), 4.16 (d, J=5 Hz, 2H), δ 3.5 (m, 5H); MS:M(H+) 501.0 (500.09).

The following compounds of Formula I are provided by this method bysubstitution ofN-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzyl-sulfanylmethyl]-3-benzylsulfanyl-propionamidewith the appropriate N-cyanomethyl propionamide:

N-Cyanomethyl-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide.(Compound 49); ¹H-NMR (DMSO) δ: 9.23 (t, J=5.4 Hz, 1H); 7.79 (m, 2H);7.67 (m, 6H); 4.72 (m, 4H); 4.18 (t, J=2.7 Hz, 2H); 3.53-3.76 (m, 5H);MS: M(+) 539.0; M(−) 536.6;

4-Benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N-cyanomethyl-butyramide(Compound 50); ¹H NMR (DMSO): 8.67 (t, J=5 Hz, 1H); 7.85 (m, 4H); 7.73(m, 2H); 7.64 (m, 4H); 4.06 (m, 2H); 3.12 (m, 4H); 2.4 (m, 1H); 1.66 (m,4H); MS: M(H+) 435.2 (434.10);

N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfonyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-propionamide(Compound 51); ¹H NMR (DMSO): 9.17 (t, J=5 Hz, 1H); 7.5-7.4 (m, 4H);7.3-7.2 (m, 4H); 7.12 (t, J=74 Hz, 2H); 4.54 (s, 4H); 4.15 (m, 2H);3.6-3.4 (m, 5H); MS: M(H+) 567.2 (566.08); and

N-Cyanomethyl-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide(Compound 52); ¹H NMR (DMSO): 9.19 (t, J=5 Hz, 1H); 7.38 (s, 10H); 4.53(d, J=14 Hz, 2H); 4.46 (d, J=14 Hz, 2H); 4.17 (t, J=3 Hz, 2H); 3.5-3.3(m, 5H); MS: M(H+) 435.2 (434.1).

The following compounds of Formula I are provided by the methodsdescribed in this application:

N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide(Compound 53); ¹H-NMR (DMSO) δ: 9.27 (t, J=6 Hz, 1H); 8.89 (d, J=6 Hz,1H); 7.4-7.2 (m, 15H); 5 (m, 1H); 4.5 (m, 4H); 4.3 (m, 2H); 3.67 (m,1H); 3.5-3.2 (m, 4H), 1.8 (m, 1H) 1.6 (m, 1H); 0.91 (t, J=7 Hz, 3H); MS:(M+) 599.0, M(−) 598.18;

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide(Compound 54); ¹H-NMR (DMSO) δ: 9.1 (t, J=6 Hz, 1H); 7.99 (d, J=8 Hz,1H); 7.88 (d, J=8 Hz, 1H); 7.7-7.2 (m, 14H); 5.35 (m, 1H); 4.6-4.4 (m,5H); 3.7-3.3 (m, 5H); 1.9 (m, 1H), 1.7 (m, 1H) 1.45 (m, 2H); 0.90 (t,J=7 Hz, 3H); MS: (M+) 599.0, M(−) 598.18;

N-Cyanomethyl-3-(2-methyl-propane-1-sulfonyl)-2-(2-methyl-propane-1-sulfonylmethyl)-propionamide(Compound 55); ¹H-NMR (DMSO) δ: 9.13 (t, J=5 Hz, 1H); 4.14 (m, 2H);3.5-3.3 (m, 5H), 3.1-2.95 (m, 4H), 2.17 (h, J=7 Hz, 2H) 1.01 (d, J=7 Hz,12H); MS: (M+) 367.0, 366.13;

Acetic acid(2S,3S)-3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-4-oxo-azetidin-2-ylester (Compound 58); ¹H NMR: (DMSO) 9.19 (d, J=5.9 Hz, 1H), 8.94 (d,J=7.6 Hz), 8.90 (d, J=7.6 Hz), 1H], 7.42-7.35 (m, 5H), 5.70 (m, 1H),4.60 (m, 1H), 4.56-4.40 (m, 2H), 3.58-3.06 (m, 11H), 2.70-2.50 (m, 2H),2.07 (s, 3H); MS: (M⁺+1) 482;

N-Cyanomethyl-3-(2-methyl-thiazol-4-ylmethylsulfonyl)-2-benzyl-sulfonylmethyl-propionamide(Compound 59); ¹H NMR (DMSO): 9.14 (t, J=5 Hz, 1H), 7.52 (s, 1H), 7.38(s, 5H), 4.64 (s, 2H), 4.53 (d, J=14 Hz, 1H), 4.46 (d, J=14 Hz, 1H),4.16 (d, J=5 Hz, 211), 3.5 (m, 5H), 2.63 (s, 3H); M=455.06, M(H+)=456.0;

N-(3-Benzenesulfonylamino-2-oxo-propyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide(Compound 60); ¹H NMR: (DMSO) 8.46 (t, J=5.2 Hz, 1H), 7.97 (t, J=5.7 Hz,1H), 7.79 (d, J=7 Hz, 2H), 7.66-7.52 (m, 3H), 7.44-7.36 (m, 5H),4.56-4.43 (m, 2H), 3.94 (d, J=5.2 Hz, 2H), 3.84 (d, J=5.7 Hz, 2H),3.59-3.04 (m, 1H), 2.75-2.55 (m, 2H); MS: (M⁺+1) 566;

3-Biphenyl-3-yl-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzyl-sulfonylmethyl]-propionamide(Compound 61); ¹H NMR: (DMSO) 8.86 (t, J=5.4 Hz, 1H), 7.70-7.10 (m,13H), 7.12 (t, J=73.7 Hz, 1H), 4.46 (s, 2H), 4.13 (m, 2H), 4.10 (d,J=5.6 Hz, 2H), 3.57 (m, 1H), 3.20-3.00 (m, 2H), 3.00-2.80 (m, 2H); MS:(M⁺+1) 499;

(3′-{2-(Cyanomethyl-carbamoyl)-3-[2-(1,1-difluoro-methoxy)-benzyl-sulfonyl]-propyl}-biphenyl-4-yl)-carbamicacid ethyl ester (Compound 62); ¹H NMR: (DMSO) 9.70 (s, 1H), 8.84 (t,J=5.4 Hz, 1H), 7.55 (s, 4H), 7.50-7.15 (m, 8H), 7.11 (t, J=73.7 Hz, 1H),4.45 (s, 2H), 4.13 (m, 2H), 4.09 (d, J=5.5 Hz, 2H), 3.56 (m, 1H),3.20-3.00 (m, 2H), 2.95-2.75 (m, 2H), 1.24 (t, J=6.9 Hz, 3H); MS: (M⁺+1)586;

N-Cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-(4′-methylsulfonylamino-biphenyl-3-yl)-propionamide(Compound 63); ¹H NMR: (DMSO) 9.77 (s, 1H), 8.79 (t, J=5.4 Hz, 1H), 7.57(d, J=8.6, 2H), 7.50-7.00 (m, 8H), 7.27 (d, J=8.6 Hz, 2H), 7.06 (t, J=73Hz, 1H), 4.40 (s, 2H), 4.04 (d, J=5.6 Hz, 2H), 3.51 (m, 1H), 3.20-3.00(m, 2H), 2.90-2.70 (m, 2H); MS: (M⁺+1) 592;

3-(3-Bromo-phenyl)-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-phenyl-methylsulfonylmethyl]-propionamide(Compound 64); ¹H NMR: (DMSO) 8.80 (t, J=5.4 Hz, 1H), 7.50-7.35 (m, 4H),7.35-7.15 (m, 4H), 7.13 (t, J=73 Hz, 1H), 4.46 (s, 2H), 4.06 (d, J=5.4Hz, 2H), 3.53 (m, 1H), 3.20-3.00 (m, 2H), 2.90-2.70 (m, 2H); MS: (W+1)501;

N-Cyanomethyl-2-((E)-3-phenyl-allyl)-3-benzylsulfonyl-propionamide(Compound 65); ¹H NMR: (DMSO) 8.85 (t, J=5.4 Hz, 1H), 7.40-7.10 (m,10H), 6.35 (d, J=15 Hz, 1H), 6.15-5.95 (m, 1H), 4.41 (s, 2H), 4.08 (d,J=5.4 Hz, 2H), 3.56-3.35 (m, 2H), 3.25-2.90 (m, 3H); MS: (M⁺+1) 383; and

N-Cyanomethyl-3-benzylsulfonyl-2-(3-phenyl-propyl)-propionamide(Compound 66); ¹H NMR: (DMSO) 8.91 (t, J=5.4 Hz, 1H), 7.45-7.10 (m,10H), 4.41 (s, 2H), 4.08 (d, J=5.4 Hz, 2H), 3.30-2.80 (m, 3H), 2.34 (t,J=7.4 Hz, 2H), 2.22-2.12 (m, 2H), 2.10-1.85 (m, 2H); MS:(M⁺+1) 385.

Example 114-Morpholin-4-yl-4-oxo-N-[1-(2-oxo-2-phenyl-acetyl)-pentyl]-2-benzylsulfonylmethyl-butyramide

2-Amino-1-(2-phenyl-[1,3]dithian-2-yl)-hexan-1-ol, prepared as inreference 12, was coupled with4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid, according tothe procedure outlined in example 8, resulting inN-{1-[Hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonyl-methyl-butyramideas a mixture of diastereomers.

N-{1-[Hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide(0.23 g, 0.35 mmol) in 9 mL acetonitrile and 2.25 mL water at 23° C. wasmixed with finely ground HgCl₂ (212 mg, 0.78 mmol) and finely groundcalcium carbonate (90 mg, 0.89 mmol). The mixture was stirred for 25minutes and then diluted with ethyl acetate. Water was added and the pHlowered to 6 by the addition of 1N HCl. After separation, the organiclayer was washed sequentially with water and brine (twice). The organicswere dried with magnesium sulfate, concentrated and chromatographed onsilica gel using a hexane-ethyl acetate gradient to afford 150 mg ofN-[1-(1-Hydroxy-2-oxo-2-phenyl-ethyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-phenyl-methylsulfonylmethyl-butyramideas a mixture of diastereomers (76% yield).

N-[1-(1-Hydroxy-2-oxo-2-phenyl-ethyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramidewas oxidized by methods described in the above examples resulting in4-morpholin-4-yl-4-oxo-N-[1-(oxo-phenyl-acetyl)-pentyl]-2-benzylsulfonylmethyl-butyramideas a mixture of diastereomers; ¹HNMR: (DMSO), 8.9 (d, J=6 Hz), ½Hdiastereomeric], 8.86 (d, J=6 Hz), ½H diastereomeric], 7.89-7.84 (m,2H), 7.7-7.67 (m, 1H), 7.56-7.5 (m, 2H), 7.4-7.3 (m, 5H), 4.56-4.54 (m,1H), 4.41-4.35 (m, 2H), 3.4-4.6 (m, 4H), 3.35-3.25 (m, 4H), 3.2-3.1 (m,2H), 2.99-2.95 (m, 1H), 1.9-1.6 (m, 2H), 1.5-1.2 (m, 6H), 1.0-0.9 (m,3H); MS: (M⁺+1) 557.

Example 123-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester

4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (120 mg, 0.34mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester(150 mg, 0.74 mmol), prepared as in reference 13, EDC (0.3 g, 1.6 mmol),and HOBt (150 mg, 0.96 mmol) were combined. Dichloromethyl (10 mL) wasadded and then 4-methylmorpholine (0.5 mL). The mixture was stirred atambient temperature for 2 hours. After dilution with ethyl acetate (200mL) the solution was washed with 1N aqueous HCl (50 mL), saturatedaqueous NaHCO₃ (50 mL) and brine (50 mL), dried with MgSO₄ andevaporated under vacuum. The crude3-hydroxy-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester was dissolved in DMSO (5 mL). Triethylamine (0.5mL) and then SO₃ pyridine complex (150 mg) were added and the mixturewas stirred at ambient temperature for 3 hours. After dilution withethyl acetate (100 mL), the solution was washed with water (50 mL) andbrine, dried with MgSO₄ and evaporated under vacuum. The residue waspurified by flash chromatography on silica gel. Eluent: 5% methanol inethyl acetate. Yield: 40 mg3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester as white solid as mixture of diastereomers; ¹HNMR: (DMSO) 8.80-8.66 (m, 1H), 7.42-7.34 (m, 5H), 4.52-4.41 (m, 2H),4.34-4.20 (m, 1H), 3.98-3.88 (m, 1H), 3.82 (d, J=18.5 Hz, 1), 3.70-3.05(m, 13H), 2.70-2.52 (m, 2H), 1.41 (s, 9H); MS: (M+H)⁺ 538.

Example 134-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylicacid benzyl ester

Sodium hydride (60% in mineral oil, 10 g, 250 mmol) was suspended in dryDMF. Allyl-carbamic acid benzyl ester (19.1 g, 100 mmol) was added dropwise at ambient temperature. After stirring for 5 minutes,5-bromo-1-pentene (25 g, 168 mmol) was added drop wise. Stirring wascontinued at 50° C. for 1 hour. The reaction was quenched with water andthen partitioned between diethyl ether and water. The ether layer waswashed with water and brine, dried with MgSO₄ and evaporated undervacuum. Flash chromatography (ethyl acetate/hexane 1:9) gave 15.5 gallyl-pent-4-enyl-carbamic acid benzyl ester.

Allyl-pent-4-enyl-carbamic acid benzyl ester (15.5 g, 59.8 mmol) wasdissolved in dichloromethyl and bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride (1 g) was added. The mixture was refluxed undera nitrogen atmosphere until TLC analysis showed complete reaction. Thesolvent was evaporated under vacuum and the residue was purified byflash chromatography (ethyl acetate/hexane 1:9). Yield: 7.8 g2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester.

To a solution of 2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzylester (4.5 g, 19.45 mmol) in dichloromethyl (50 mL) was addedm-chloroperbenzoic acid (60 mmol). The mixture was stirred at ambienttemperature for 16 hours. Saturated aqueous K₂CO₃ solution was added andthe mixture was extracted with dichloromethyl. The combined organiclayers were washed with saturated aqueous NaHCO₃ and brine, dried withMgSO₄ and evaporated under vacuum. The crude epoxide was dissolved in a8:1 methanol/water mixture (100 mL). Ammonium chloride (3.2 g, 60 mmol)and sodium azide (3.9 g, 60 mmol) was added and the mixture was heatedat 60° C. for 48 hours. Most of the solvent was removed under vacuum.The residue was extracted with ethyl acetate. The combined organiclayers were washed with saturated aqueous NaHCO₃ (200 mL) and brine (200mL), dried with MgSO₄ and evaporated under vacuum. Flash chromatographyof the residue (hexane/ethyl acetate 3:1) gave 3.3 g of4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester.

To a solution of 4-azido-3-hydroxy-azepane-1-carboxylic acid benzylester (3.3 g, 11.37 mmol) in methanol (50 mL) was added triethylamine (5mL) and 1,3-propanedithiol (3.42 mL, 35 mmol). The mixture was stirredat ambient temperature until TLC analysis showed complete consumption ofthe starting material. A white precipitate was removed by filtration andthe filtrate was evaporated to dryness. The residue was triturated witha 1:1 hexane/diethyl ether mixture to remove excess dithiol and driedunder vacuum.

The crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester wascoupled to 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acidand oxidized, as described above, to yield4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylicacid benzyl ester; ¹H NMR: (DMSO) 8.46-8.42 (m, 1H), 7.44-7.24 (m, 10H),5.18-5.04 (m, 2H), 4.52-4.33 (m, 4H), 4.04-3.76 (m, 2H), 3.58-3.30 (m,11H), 3.11-3.03 (m, 1H), 2.96-2.78 (m, 1H), 2.72-2.57 (m, 1H), 1.84-1.55(m, 4H); MS: (M+H)⁺ 600.

Example 14N-(1,1-Dimethyl-2-oxazolo[4,5-b]pyridin-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (142 mg, 0.4mmol), 2-amino-2-methyl-1-oxazolo[4,5-b]pyridin-2-yl-propan-1-one TFAsalt (165 mg), prepared as in reference 14, and HOBt (73 mg, 0.45 mmol)in MeCl₂ (5 ml) was added EDC (115 mg, 0.6 mmol) and N-methylmorpholine(0.25 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated. Theresidue was purified by silica gel column chromatography to yield 92 mgofN-{1-[(5-Ethyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-butyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide.

This amide was treated with Dess-Martin periodinane (125.6 mg, 0.254mmol) at room temperature. After stirring for 1 hour, 5 ml of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 31 mg ofN-(1,1-dimethyl-2-oxazolo[4,5-b]pyridin-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benyzlsulfonylmethyl-butyramide;H¹ NMR(DMSO-d): 9.36(1H, s, NH), 8.68(1H, d, J=4.7 Hz), 8.34(1H, d,J=8.42 Hz), 7.62(1H, dd, J=4.7 Hz, J=8.42 Hz), 7.4-7.4(5H, m),4.41-4.3(2H, s), 3.5-3(12H, m), 2.2-2.1(1H, m), 1.6(3H, s), 1.51(3H, s);MS: 541.4(M−1), 543.4(M+1).

Example 15N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (177.7 mg,0.5 mmol), 2-amino-1-(5-ethyl-1,3,4-oxadiazole-2-yl)-1-pentanol HCl salt(117.5 mg), and HOBt (91.8 mg, 0.6 mmol) in MeCl₂ (5 ml), was added EDC(144 mg, 0.75 mmol) and N-methylmorpholine (0.3 ml) at room temperature.After stirring for 14 hours, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃,brine, dried with MgSO₄ and concentrated to yield 240 mg of crudeproduct (MS: 536(M−1), 538.4(M+1)). Without further purification, thecrude product was treated with Dess-Martin periodinane (334 mg, 0.67mmol) at room temperature in 5 mL of MeCl₂. After stirring for 1 hour, 5mls of saturated Na₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours,the reaction mixture was extracted with ethyl acetate, washed withbrine, dried with MgSO₄ and concentrated. The residue was purified withsilica gel column chromatography to yield 110 mg ofN-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;H¹ NMR(DMSO-d): 8.84(½H, d, NH, diastereomeric), 8.78( 1/1H, d, NH,diastereomeric), 7.45-7.2(5H, m), 5.05-4.9(1H, m), 4.48-4.3(2H, m),3.6-3.4(4H, m), 3.4-3.2(4H, m), 3.1-2.4(6H, m), 1.9-1.75(1H, m),1.7-1.55(2H, m), 1.25-1.2(2H, m), 1.2-1.1(3H, m), 0.9-0.8(3H, m); MS:534M−1), 535.8(M+1).

Example 16N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide

To a stirred mixture4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (176.5 mg,0.5 mmol), 2-amino-1-(5-ethyl-1,3,4-oxadiazole-2-yl)-1-pentanol HCl salt(117.5 mg), and HOBt (91.8 mg, 0.6 mmol) in MeCl₂ (5 ml), was added EDC(144 mg, 0.75 mmol) and N-methylmorpholine (0.3 ml) at room temperature.After stirring for 14 hours, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃,brine, dried with MgSO₄ and concentrated to yield 270 mg of crudeproduct; MS: 534.1(M−1), 535.7(M+1).

The amide was then treated with Dess-Martin periodinane (378.7 mg, 0.675mmol) at room temperature in 5 ml of MeCl₂. After stirring for 1 hour, 5ml of saturated Na₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours,the reaction mixture was extracted with ethyl acetate, washed withbrine, dried with MgSO₄ and concentrated. The residue was purified withsilica gel column chromatography to yield 165 mg ofN-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzyl-sulfonyl-methyl-4-piperidin-1-yl-butyramide;H¹ NMR (DMSO-d): 8.85(½H, d, NH, diastereomeric), 8.78(½, d, NH,diastereomeric), 7.4-7.2(5H, m), 5.1-4.9(1H, m), 4.5-4.3(2H, m),3.5-3.2(8H, m), 3.1-2.6(1H, m), 2.9(2H, m), 1.9-1.6(2H, m), 1.6-1.2(8H,m), 1.24(3H, m), 0.9-0.8(3H, m); MS: 531.6(M−1), 533.4(M+1).

Example 17N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide

To a stirred mixture 4-cyclopentyl-4-oxo-2-benzylsulfonylmethyl-butyricacid (169.5 mg, 0.5 mmol),2-amino-1-(5-ethyl-1,3,4-oxadiazole-2-yl)-1-pentanol HCl salt (117.5mg), and HOBt (91.8 mg, 0.6 mmol) in MeCl₂ (5 ml), was added EDC (144mg, 0.75 mmol) and N-methylmorpholine (0.3 ml) at room temperature.After stirring for 14 hours, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃,brine, dried with MgSO₄ and concentrated to yield 240 mg of crudeproduct. The crude product was treated with Dess-Martin periodinane (343mg, 0.693 mmol) at room temperature in 5 mls of MeCl₂. After stirringfor 1 hour, 5 mls of saturated Na₂S₂O₃—NaHCO₃ were added. After afurther 0.5 hours, the reaction mixture was extracted with ethylacetate, washed with brine, dried with MgSO₄ and concentrated. Theresidue was purified with silica gel column chromatography to yield 145mg ofN-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide;H¹NMR(DMSO-d): 8.85(½H, d, NH, diastereomeric), 8.78(½H, d, NH,diastereomeric), 7.5-7.3(5H, m), 5.1-4.95(1H, m), 4.5-4.3(2H, m),3.5-3.2(8H, m), 3.2-3(1H, m), 2.82(2H, m), 2-1.8(6H, m), 1.6-1.3(2H, m),1.24(3H, m), 0.9-0.8(3H, m); MS: 518.2(M−1), 519.7(M+1).

Example 18N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (230 mg, 0.65mmol), 2-amino-1-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-butan-1-one TFAsalt (204 mg), prepared as in reference 15, and HOBt (119 mg, 0.78 mmol)in MeCl₂ (5 ml), was added EDC (187 mg, 0.98 mmol) andN-methylmorpholine (0.35 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated to yield 82 mg ofN-{1-[Hydroxy-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonyl-methyl-butyramide;MS: 537.6(M−1), 539.8(M+1).

This amide then was treated with Dess-Martin periodinane (111 mg, 0.149mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ was added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 13 mgs ofN-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonyl-methyl-butyramide;H¹ NMR(CDCl₃): 7.8, 7.5(1H, d,d NH, diastereomeric), 7.4-7.2(5H, m),5.3-5.1(1H, m), 4.6(2H, s, OCH₂), 4.3-4.1(3H, m), 3.8-3.1(13H, m),3-2.4(2H, m), 2.2-1.5(2H, m), 0.95(3H, t); MS: 535.7(M−1), 537.5(M+1).

Example 19N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (229 mg, 0.65mmol), 2-amino-1-(5-methoxymethyl-1,3,4-oxadiazole-2-yl)-1-propanol TFAsalt (204 mg), prepared as in reference 15, and HOBt (119 mg, 0.78 mmol)in MeCl₂ (5 ml), was added EDC (187 mg, 0.98 mmol) andN-methylmorpholine (0.35 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated to yield 130 mg ofN-{1-[hydroxy-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide;MS: 535.4(M−1), 537.7(M+1).

The amide then was treated with Dess-Martin periodinane (180 mg, 0.364mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 26 mgs ofN-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide;H¹ NMR(CDCl₃): 8, 7.7(1H, d,d, NH, diastereomeric), 7.4-7.2(5H, m),5.3-5.1(1H, m), 4.6(2H, s, OCH₂), 4.3-4.1(3H, m), 3.8-3.2(9H, m),3-2.4(2H, m), 2.2-1.4(8H, m), 0.95(3H, t); MS: 535.7(M+1).

Example 20N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (220 mg,0.65 mmol), 2-amino-1-(5-methoxymethyl-1,3,4-oxadiazole-2-yl)-1-propanolTFA salt (204 mg), prepared as in reference 15, and HOBt (119 mg, 0.78mmol) in MeCl₂ (5 ml), was added EDC (187 mg, 0.98 mmol) andN-methylmorpholine (0.35 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated to yield 84 mg ofN-{1-[Hydroxy-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 521.6(M−1), 523.2(M+1).

This amide was treated with Dess-Martin periodinane (114 mg, 0.153 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 17 mg ofN-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbon-yl-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide;H¹ NMR(CDCl₃): 8.2, 8(1H, d,d, NH, diastereomeric), 7.6-7.2(5H, m),5.3-5.1 (1H, m), 4.6(2H, s, OCH₂), 4.3-4.1(3H, m), 3.8-3.2(9H, m),3-2.4(2H, m), 2.2-1.4(6H, m), 0.95(3H, t); MS: 519.6(M−1), 521.6(M+1).

Example 214-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (177 mg, 0.5mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(175 mg), prepared as in reference 16, and HOBt (92 mg, 0.6 mmol) inMeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine(0.35 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield308 mg ofN-{1-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 569.6(M−1), 571.4(M+1).

This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 224 mg of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;H¹ NMR(DMSO-d): 8.9, 8.84 (1H, d, d, NH, diastereomeric), 8.1-8(2H, m),7.7-7.6(3H, m), 7.4-7.3(5H, m), 5.1-4.9(1H, m), 4.5-4.3(2H, m),3.6-3.3(11H, m), 3.12-3(1H, m), 2.65-2.5(1H, m), 2-1.9(1H, m),1.8-1.7(1H, m), 0.96(3H, t); MS: 567.6(M−1), 569.4(M+1).

Example 224-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-piperidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (177 mg, 0.5mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(175 mg), prepared as in reference 16, and HOBt (92 mg, 0.6 mmol) inMeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine(0.35 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield284 mg ofN-{1-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-henylmethylsulfonylmethyl-4-piperidin-1-yl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 567.6(M−1), 569.6(M+1).

This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 237 mg of4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-piperidin-1-yl-butyramide;H¹NMR (DMSO-d): 8.9, 8.84 (1H, d, d, NH, diastereomeric), 8.1-8(2H, m),7.7-7.6(3H, m), 7.4-7.3(5H, m), 5.1-4.9(1H, m), 4.5-4.3(2H, m),3.4-3.1(7H, m), 3.12-3(1H, m), 2.65-2.5(1H, m), 2-1.9(1H, m),1.8-1.7(1H, m), 1.6-1.2(6H, m), 0.96(3H, t); MS: 565.4(M−1), 567.6(M+1).

Example 234-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide

To a stirred mixture of4-Oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (170 mg, 0.5mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(175 mg), prepared as above, and HOBt (92 mg, 0.6 mmol) in MeCl₂ (5 ml),was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine (0.35 ml) atroom temperature. After stirring for 14 hours, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield 280mg ofN-{1-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-henylmethylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 553.6(M−1), 555.4(M+1).

This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 200 mg of4-oxo-2-benyzlsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide;H¹ NMR (DMSO-d): 8.9, 8.84 (1H, d, d, NH, diastereomeric), 8.1-8(2H, m),7.7-7.6(3H, m), 7.4-7.3(5H, m), 5.1-4.9(1H, m), 4.5-4.3(2H, m),3.4-3.1(7H, m), 3.12-3(1H, m), 2.65-2.5(1H, m), 2.1-1.6(6H, m), 0.96(3H,t); MS: 551.6(M−1), 553.6(M+1).

Example 244-Morpholin-4-yl-N-[1-(oxazolo[4,5-b]_(pyridine-)2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (177 mg, 0.5mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(175 mg), prepared as in reference 17, and HOBt (92 mg, 0.6 mmol) inMeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine(0.35 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield308 mg ofN-[1-(Hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide;MS: 543.6 (M−1), 545.6(M+1)

This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 224 mg of4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide;H¹ NMR (DMSO-d): 8.96, 8.85(1H, d,d, NH, diastereomeric), 8.75-8.7(1H,m), 8.42-8.3(1H, m), 7.7-7.6(1H, m), 7.4-7.3(5H, m), 5.15-5.04(1H, m),4.5-4.3(2H, m), 3.6-3.2(1H, m), 3.15-3.0(1H, m), 2.7-2.5(1H, m),2.1-1.9(1H, m), 1.8-1.7(1H, m), 0.98(3H, t); MS: 541.2(M−1), 543.2(M+1).

Example 25N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (177 mg, 0.5mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(175 mg), prepared as in reference 17, and HOBt (92 mg, 0.6 mmol) inMeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine(0.35 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield284 mg ofN-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-4-oxo-2-henylmethylsulfonylmethyl-4-piperidin-1-yl-butyramide;MS: 541.6 (M−1), 543.4(M+1).

This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 237 mg ofN-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide;H¹ NMR DMSO-d): 8.93, 8.83(1H, d,d, NH, diastereomeric), 8.75-8.72(1H,m), 8.4-8.37(1H, m), 7.7-7.6(1H, m), 7.4-7.3(5H, m), 5.15-5(1H, m),4.5-4.3(2H, m), 3.45-3.2(9H, m), 3.1-3(1H, m), 2.67-2.5(1H, m),2.1-1.9(1H, m), 1.84-1.7(1H, m), 1.6-1.5(2H, m), 1.5-1.3(4H, m),0.98(3H, t); MS: 539.4(M−1), 541.2(M+1).

Example 26N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (170 mg, 0.5mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(175 mg), prepared as in reference 17, and HOBt (92 mg, 0.6 mmol) inMeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine(0.35 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield280 mg ofN-[1-(Hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-4-oxo-2-henylmethylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 527.6(M−1), 529.4(M+1).

This amide was treated with Dess-Martin periodinane (371 mg, 0.75 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 200 mg ofN-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide;H¹ NMR (DMSO-d): 8.96, 8.87(1H, d,d, NH, diastereomeric), 8.75-8.72(1H,m), 8.45-8.3(1H, m), 7.7-7.6(1H, m), 7.45-7.3(5H, m), 5.2-5(1H, m),4.5-4.3(2H, m), 3.5-3.15(7H, m), 3.15-3(1H, m), 2.55-2.4(1H, m),2.1-1.95(1H, m), 1.9-1.6(5H, m), 0.98(3H, t); MS: 525.2(M−1),526.8(M+1).

Example 274-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (106.5 mg,0.3 mmol), 2-Amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-olTFA salt (105 mg), prepared as in reference 18, and HOBt (55 mg, 0.36mmol) in MeCl₂ (5 ml), was added EDC (86.4 mg, 0.45 mmol) andN-methylmorpholine (0.25 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated, yield 176 mg ofN-{1-[hydroxy-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide.MS: 568.4(M−1), 570(M+1)

This amide was treated with Dess-Martin periodinane (222.7 mg, 0.45mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 84 mg of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;H¹ NMR(DMSO-d): 8.95-8.85(3H, m), 8.1-8(2H, m), 7.44-7.3(5H, m),5-4.9(1H, m), 4.5-4.3(2H, m), 3.4-3.(8H, m), 2.7-2.5(1H, m),2.05-1.9(1H, m), 1.8-1.6(1H, m), 1.6-1.2(6H, m), 0.98(3H, t); MS:566.6(M−1), 568.6(M+1).

Example 284-Oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (105.9 mg,0.3 mmol), 2-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-olTFA salt (105 mg), prepared as in reference 18, and HOBt (55 mg, 0.36mmol) in MeCl₂ (5 ml), was added EDC (86.4 mg, 0.45 mmol) andN-methylmorpholine (0.25 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated to yield 176 mg ofN-{1-[Hydroxy-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonyl-methyl-butyramide;MS: 570.2(M−1), 572(M+1).

This amide was treated with Dess-Martin periodinane (222.7 mg, 0.45mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 78 mg of4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;H¹NMR(DMSO-d): 9.0-8.85(3H, m), 8.1-8(2H, m), 7.44-7.3(5H, m), 54.9(1H,m), 4.5-4.3(2H, m), 3.6-3.2(1H, m), 3.15-3.05(1H, m), 2.7-2.5(1H, m),2.05-1.9(1H, m), 1.8-1.7(1H, m), 0.96(3H, t); MS: 568.6(M−1),570.6(M+1).

Example 294-Oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (102 mg, 0.3mmol), 2-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol TFAsalt (105 mg), prepared as in reference 18, and HOBt (55 mg, 0.36 mmol)in MeCl₂ (5 ml), was added EDC (86.4 mg, 0.45 mmol) andN-methylmorpholine (0.25 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated to yield 210 mg ofN-{1-[Hydroxy-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide.MS: 554.2(M−1), 555.8(M+1).

This amide was treated with Dess-Martin periodinane (222.7 mg, 0.45mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 102 mg of4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl-4-pyrrolidin-1-yl-butyramide;H¹ NMR (DMSO-d): 9.0-8.85(3H, m), 8.1-8(2H, m), 7.44-7.3(5H, m),5.05-4.9(1H, m), 4.55-4.35(2H, m), 3.4-3.(8H, m), 2.6-2.4(1H, m),2.05-1.9(1H, m), 1.9-1.6(5H, m), 0.96(3H, t); MS: 552.6(M−1),554.6(M+1).

Example 304-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-3-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide

To a stirred mixture of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (177.7 mg,0.5 mmol), 2-amino-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-butan-1-olTFA salt (180 mg), prepared as in reference 19, and HOBt (92 mg, 0.6mmol) in MeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol) andN-methylmorpholine (0.25 ml) at room temperature. After stirring for 14hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated, yield 210 mg ofN-{1-[Hydroxy-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 570.4(M−1), 572.4(M+1).

This amide was treated with Dess-Martin periodinane (277 mg, 0.56 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 110 mg of4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-3-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide;H¹ NMR(DMSO-d: 9.23(1H, s), 8.94, 8.88(1H, d,d, NH, diastereomeric),8.87-8.8(1H, m), 8.46-8.4(1H, m), 7.7-7.6(1H, m), 7.4-7.25(5H, m),5.05-4.9(1H, m), 4.55-4.3(2H, m), 3.6-3.15(1H, m), 3.14-3(1H, m),2.7-2.5(1H, m), 2.05-1.9(1H, m), 1.8-1.65(1H, m), 0.98(3H, t); MS:568.5(M−1), 570.3(M+1).

Example 31N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (141 mg, 0.4mmol), 2-amino-1-benzooxazol-2-yl-butan-1-ol TFA salt. (129 mg),prepared as in reference 20, and HOBt (74 mg, 0.48 mmol) in MeCl₂ (5ml), was added EDC (115 mg, 0.6 mmol) and N-methylmorpholine (0.25 ml)at room temperature. After stirring for 14 hours, the reaction mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield 157mg ofN-[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-4-oxo-2-enylmethylsulfonylmethyl-4-piperidin-1-yl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 540.4(M−1), 542.6(M+1).

This amide was treated with Dess-Martin periodinane (215.3 mg, 0.435mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 103.3 mg ofN-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide;H¹ NMR(DMSO-d): 8.84, 8.76(1H, d,d, J=5.6 Hz, J=6.4 Hz, NH,diastereomeric), 8.02-7.96(1H, m), 7.92-7.86(1H, m), 7.68-7.62(1H, m),7.58-7.52(1H, m), 7.44-7.32(5H, m), 5.24-5.12(1H, m), 4.52-4.38(2H, m),3.5-3.22(7H, m), 3.12-3.02(1H, m), 2.64-2.52(1H, m), 2.04-1.94(1H, m),1.8-1.68(1H, m), 1.6-1.48(2H, m), 1.48-1.32(4H, m), 0.98(3H, t, J=7.6Hz); MS: 540.4(M+1).

Example 32N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide

To a stirred mixture of4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (135.6 mg,0.4 mmol), 2-amino-1-benzooxazol-2-yl-butan-1-ol TFA salt (129 mg),prepared as in reference 20, and HOBt (73.4 mg, 0.48 mmol) in MeCl₂ (5ml), was added EDC (115.2 mg, 0.6 mmol) and N-methylmorpholine (0.25 ml)at room temperature. After stirring for 14 hours, the reaction mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield 260mg ofN-[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-4-oxo-2-henylmethylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide.Without further purification, the crude product was used for nextreaction; MS: 526.6(M−1), 528.6(M+1).

This amide was treated with Dess-Martin periodinane (215 mg, 0.435 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 199 mg ofN-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide;H¹ NMR(DMSO-d): 8.87, 8.79(1H, d,d, NH, J=6 Hz, J=6.4 Hz,diastereomeric), 8.04-7.96(1H, m), 7.92-7.86(1H, m), 7.68-7.62(1H, m),7.58-7.5(1H, m), 7.44-7.32(5H, m), 5.25-5.14(1H, m), 4.52-4.38(2H, m),3.5-3.04(7H, m), 3.03-3.01(1H, m), 2.52-2.4(1H, m), 2.05-1.9(1H, m),1.9-1.65(5H, m), 0.98(3H, m); MS: 526.3(M+1).

Example 33N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide

To a stirred mixture of2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (84.9 mg, 0.3mmol), 2-amino-1-benzooxazol-2-yl-butan-1-ol TFA salt (96.9 mg),prepared as in reference 21, and HOBt (55.1 mg, 0.36 mmol) in MeCl₂ (5ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine (0.25 ml)at room temperature. After stirring for 14 hours, the reaction mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield 150mg ofN-[1-(benzooxazol-2-yl-hydroxy-methyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;MS: 470.5(M−1), 472.4(M+1).

This amide was treated with Dess-Martin periodinane (237.6 mg, 0.48mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 76 mg ofN-[1-(benzooxazole-2-carbonyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide;H¹ NMR(DMSO-d): 8.49(1H, d, J=5.2 Hz, NH), 7.96(1H, d, J=7.6 Hz),7.86(1H, d, J=8.4), 7.6(1H, m), 7.5(1H, m), 5.14-5.04(1H, m),3.6-3.25(8H, m), 2.9-2.75(1H, m), 2.5-2.4(1H, m), 2.25-2.15(1H, m),2-1.8(1H, m), 1.8-1.7(2H, m), 1.7-1.6(1H, m), 1.6-1.4(5H, m),1.35-1.2(1H, m), 1.2-1(4H, m), 0.96(3H, t); MS: 468.6(M−1), 470.5(M+1),492.3(M+Na).

Example 342-Cyclohexylmethyl-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide

To a stirred mixture of2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (84.9 mg, 0.3mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt(97.5 mg), prepared as in reference 21, and HOBt (55.1 mg, 0.36 mmol) inMeCl₂ (5 ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine(0.25 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield153 mg of2-cyclohexylmethyl-N-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide;MS: 471.6(M−1), 473.3(M+1).

This amide was treated with Dess-Martin periodinane (237.6 mg, 0.48mmol) at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 95 mg of2-cyclohexylmethyl-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide;H¹NMR(DMSO-d): 8.72-8.68(1H, m), 8.6(1H, d, J=5.2 Hz, NH), 8.4-8.34(1H,m), 7.68-7.59(1H, m), 5.2-4.96(1H, m), 3.5-3.45(8H, m), 2.58(1H, m),2.5-2.4(1H, m), 2.45-2.15(1H, m), 2.05-1.9(1H, m), 1.85-1.65(2H, m),1.6-1.4(5H, m), 1.3-1.2(1H, m), 1.25-1(4H, m), 0.97(3H, t); MS:469.6(M−1), 471.4(M+1), 493.2(M+Na).

Example 352-Cyclohexylmethyl-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide

To a stirred mixture of2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (84.9 mg, 0.3mmol), 2-amino-1-(5-ethyl-1,3,4-oxadiazole-2-yl)-1-pentanol HCl salt(70.5 mg), prepared as in reference 21, and HOBt (55.1 mg, 0.36 mmol) inMeCl₂ (5 ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine(0.25 ml) at room temperature. After stirring for 14 hours, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated NaHCO₃, brine, dried with MgSO₄ and concentrated to yield142 mg of2-cyclohexylmethyl-N-{1-[(5-ethyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-butyl}-4-morpholin-4-yl-4-oxo-butyramide;MS: 463.5(M−1), 465.3(M+1).

This amide was treated with Dess-Martin periodinane (239 mg, 0.48 mmol)at room temperature. After stirring for 1 hour, 5 mls of saturatedNa₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, the reactionmixture was extracted with ethyl acetate, washed with brine, dried withMgSO₄ and concentrated. The residue was purified with silica gel columnchromatography to yield 65 mg of2-cyclohexylmethyl-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide;H¹ NMR (DMSO-d): 8.6, 8.51(1H, dd, J=6.8 Hz, J=5.6 Hz, NH,diastereomeric), 4.98(4.88(1H, m), 3.6-3.25(8H, m), 3-2.9(2H, q, J=7.6Hz), 2.9-2.75(1H, m), 2.5-2.4(1H, m), 2.3-2.1(1H, m), 1.9-1.7(2H, m),1.7-1.4(7H, m), 1.4-1.2(2H, m), 1.28(3H, t), 1.2-1(6H, m), 0.88(3H, t);MS: 461.4(M−1), 463.4(M+1), 485.4(M+Na).

Example 36N-(2-Benzooxazol-2-yl-1-methoxymethyl-2-oxo-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide

To a stirred mixture of2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyricacid (210.5 mg, 0.5 mmol),2-amino-1-benzooxazol-2-yl-3-methoxy-propan-1-ol (112.5 mg), and HOBt(91.8 mg, 0.6 mmol) in MeCl₂ (5 ml), was added EDC (144 mg, 0.75 mmol)and N-methylmorpholine (0.35 ml) at room temperature. After stirring for14 hours, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃, brine, dried with MgSO₄and concentrated to yield 301 mg ofN-(2-benzooxazol-2-yl-2-hydroxy-1-methoxymethyl-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;MS: 624.5(M−1), 626.3(M+1).

This amide (150 mg, 0.24 mmol) was treated with Dess-Martin periodinane(178 mg, 0.36 mmol) at room temperature. After stirring for 1 hour, 5 mlof saturated Na₂S₂O₃—NaHCO₃ were added. After a further 0.5 hours, thereaction mixture was extracted with ethyl acetate, washed with brine,dried with MgSO₄ and concentrated. The residue was purified with silicagel column chromatography to yield 39 mg ofN-(2-Benzooxazol-2-yl-1-methoxymethyl-2-oxo-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide;H¹ NMR(DMSO-d): 8.97, 8.8(1H, dd, J=5.6 Hz, J=5.6 Hz, NH,diastereomeric), 8.02-7.94(1H, m), 7.9-7.84(1H, m), 7.66-7.58(1H, m),7.55-7.38(3H, m), 7.3-7.18(2H, m), 7.1(1H, t, J=73.6 Hz), 5.54-5.42(1H,m), 4.6-4.4(4H, m), 3.92-3.84(1H, m), 3.82-3.72(1H, m), 3.68-3.1 (11H,m), 2.7-2.56(1H, m), 1.7-1.55(1H, m), 1.3-1(1H, m); MS: 622.4(M−1),624.3(M+1), 646.3(M+Na).

Example 37N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyramide

¹H NMR: (DMSO) 8.47 (d, J=6 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.86 (d,J=8.2 Hz, 1H), 7.59 (t, J=8.2 Hz, 1H), 7.51 (t, J=8.2 Hz, 1H), 5.09-5.03(m, 1H), 3.56-3.27 (m, 8H), 2.72-2.64 (m, 1H), 2.54-2.46 (m, 1H), 2.21(dd, J=15.8 Hz, J=5.3 Hz, 1H), 1.99-1.89 (m, 1H), 1.76-1.65 (m, 1H),1.60-0.95 (m, 13H), 0.96 (t, J=7 Hz, 3H), 0.72-0.60 (m, 2H). MS: (M+H)⁺484.

Example 382-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide

¹H NMR: (DMSO) 8.71-8.68 (m, 1H), 8.58 (d, J=4.7 Hz, 1H), 8.36 (d, J=8.5Hz, 1H), 7.66-7.61 (m, 1H), 5.00-4.93 (m, 1H), 3.56-3.26 (m, 8H),2.72-2.63 (m, 1H), 2.54-2.44 (m, 1H), 2.20 (dd, J=15.8 Hz, J=5.3 Hz,1H), 2.02-1.92 (m, 1H), 1.78-1.67 (m, 1H), 1.60-0.95 (m, 13H), 0.97 (t,J=7 Hz, 3H), 0.68-0.57 (m, 2H). MS: (M+H)⁺ 485.

Example 392-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide

¹H NMR: (DMSO) 8.54 (d, J=4.7 Hz, 1H), 8.10-8.04 (m, 2H), 7.70-7.58 (m,3H), 4.91-4.85 (m, 1H), 3.55-3.22 (m, 8H), 2.70-2.62 (m, 1H), 2.56-2.45(m, 1H), 2.22 (dd, J=15.5 Hz, J=5 Hz, 1H), 1.98-1.88(m, 1H),1.77-1.66(m, 1H), 1.60-0.95(m, 13H), 0.96(t, J=7 Hz, 3H), 0.75-0.60 (m,2H). MS: (M+H)⁺ 511.

Example 402-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide

1:1 Mixture of diastereomers. ¹H N: (DMSO), 8.89 (d, J=5.6 Hz), 8.82 (d,J=6 Hz) 1H], 8.08-8.03 (m, 2H), 7.70-7.18 (m, 7H), 7.11 (t, JH,F=74 Hz),7.08 (t, JH,F=74 Hz) 1H], 5.01-4.90 (m, 1H), 4.56-4.43 (m, 2H),3.56-3.13 (m, 10H), 2.68-2.40 (m, 3H), 2.00-1.90 (m, 1H), 1.78-1.68 (m,1H), 0.96 (t, J=7 Hz, 3H). MS: (M+H)⁺ 635.

Example 412-(2-Difluoromethoxy-benzylsulfonylmethyl)-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide

1:1 Mixture of diastereomers. ¹H NMR: (DMSO), 8.82 (d, J=5.5 Hz), 8.77(d, J=5 Hz) 1H], 7.51-7.42 (m, 2H), 7.30-7.19 (m, 2H), 7.11 (t, JH,F=74Hz), 7.10 (t, JH,F=74 Hz) 1H], 5.02-4.92 (m, 1H), 4.56-4.43 (m, 2H),3.58-3.26 (m, 10H), 3.20-3.12 (m, 1H), 2.98-2.89 (m, 2H), 2.68-2.44 (m,2H), 1.86-1.76 (m, 1H), 1.69-1.58 (m, 1H), 1.46-1.20 (m, 5H), 0.88 (t,J=7 Hz, 3H). MS: (M+H)⁺ 601.

Example 42N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-difluoromethoxy-benzyl-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide

1:1 Mixture of diastereomers. ¹H NMR: (DMSO), 8.85 (d, J=5.3 Hz), 8.76(d, J=5.3 Hz) 1H], 7.97 (t, J=6.5 Hz, 1H), 7.89-7.84 (m, 1H), 7.64-7.18(m, 6H), 7.12 (t, JH,F=74 Hz), 7.10 (t, JH,F=74 Hz) 1H], 5.22-5.11 (m,1H), 4.56-4.42 (m, 2H), 3.58-3.12 (m, 11H), 2.67-2.42 (m, 2H), 2.02-1.92(m, 1H), 1.78-1.66 (m, 1H), 0.96 (t, J=7 Hz, 3H). MS: (M+H)⁺ 608.

Example 43 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,1-(benzooxazole-2-carbonyl)-propyl]-amide

2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid (83.7 mg, 0.274mmol), prepared as in reference 25, and HOBT (62.9 mg, 0.466 mmol) wereadded to a suspension of PS-bound N-Cyclohexylcarbodiimide (HL 200-400mesh cross linked with 2% DVB) from Novabiochem (322.3 mg, 0.548 mmol,1.7 mmol/g loading) in methylene chloride (8 ml) and stirred at roomtemperature for 15 minutes. 2-Amino-1-benzooxazol-2-yl-butan-1-ol (56.5mg. 0.274 mmol), prepared as in reference 20, was added and the reactionmixture stirred overnight at room temperature. Silicycle trisamine-3(380.5 mg, 1.37 mmol, 3.6 mmol/g loading) was added and stirred foranother 2 hours. The mixture was filtered and the filtrate evaporatedunder reduced pressure to give2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,1-(benzooxazol-2-yl-hydroxy-methyl)-propyl]-amide as a yellow solid (128mg).

To a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid, 1-(benzooxazol-2-yl-hydroxy-methyl)-propyl]-amide (128 mg, 0.259mmol) in methylene chloride (5 ml), Dess-Martin Periodinane (0.519 mmol,220 mg) was added and stirred at room temperature for 90 minutes. Thereaction mixture was washed with a solution of Na₂S₂O₃ in saturatedNaHCO₃, dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by chromatography, eluting with a mixture of ethylacetate and heptane, to give2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,1-(benzooxazole-2-carbonyl)-propyl]-amide as a mixture ofdiastereoisomers (77 mg); ¹H NMR (CDCl₃) 7.90 (d, J=8 Hz, 1H), 7.65 (d,J=8.2 Hz, 1H), 7.55 (t, J=7.3 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.4-7.1(m, 5H), 7.0 (d, J=7.4 Hz), 6.76 (d, J=7.1 Hz), 1H], 5.60 (m, 1H),3.8-3.4 (m, 8H), 3.1-2.5 (m, 4H), 2.4-2.1 (m, 2H), 2.0-1.6 (m, 4H), 1.5(m, 1H), 1.1 (m, 3H). MS: 492 (MH⁺).

Example 44(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide

Similarly prepared according to the general procedure given for Example43 but using (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid,prepared as described in reference 21, and(S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol, prepared asin reference 26; MS: 519 (M+Na), LC-MS retention time 4.5 min; ¹H NMR(CDCl₃) 8.19 (d, J=7 Hz, 2H), 7.65-7.51 (m. 3H), 6.64 (d, J=7 Hz, 1H),5.44-5.38 (m, 1H), 3.69-3.38 (m, 8H), 3.05-2.98 (m, 1H), 2.76 (dd, J=16Hz & 10 Hz, 1H), 2.26 (dd, J=16 Hz & 3 Hz, 1H), 2.10 (m, 1H), 1.80 (m,1H), 1.75-1.59 (m, 6H), 1.28-1.13 (m, 5H), 1.03-0.98 (t, J=7 Hz, 3H),0.92-0.81 (m, 2H).

Example 45 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,(S)-1-(5-phenyl-[1,2,4]oxadiazole-3-carbonyl)-propyl]-amide

Similarly prepared according to the procedure for Example 43 but using2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and(S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol; MS: 541(M+Na), LCMS retention time 4.44 and 4.53 min; ¹H NMR (CDCl₃) 8.18 (d,J=7 Hz, 2H), 7.69-7.51 (m, 3H), 7.27-7.10 (m, 5H), 6.99-6.7 (d, J=7 Hz,1H), 5.38 (m, 1H), 3.70-3.36 (m, 8H), 2.99-2.56 (m, 4H), 2.27 (m, 1H),2.11 (m, 1H), 1.87-1.60 (m, 4H), 1.44 (m, 1H), 1.02-0.97(dt, J=7 Hz,3H).

Example 464-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide

Similarly prepared according to the procedure for Example 43 but using4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid and(S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol; MS: 569(MH⁺), LCMS retention time 4.1 min; ¹H NMR (CDCl₃) 8.18 (d, J=7.9 Hz,2H), 7.74-7.31 (m, 9H), 5.27 (m, 1H), 4.25 (m, 2H), 3.71-3.41 (m, 8H),2.95 (m, 1H), 2.78-2.70 (m, 2H), 2.10 (m, 1H), 1.85 (m, 1H), 1.0 (m,3H).

Example 47(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide

Similarly prepared according to the general procedure given for Example43 above but using (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyricacid and (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol; MS:497 (MH⁺).

Example 484-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide

Compound 104 was synthesized according to the following reactionprotocol:

Compound 1 (0.1066 g, 0.3 mmol) and compound 2 (0.0806 g, 0.3 mmol) weremixed with EDC (0.0633 g, 0.33 mmol), HOBT (0.0446 g, 0.33 mmol) andDIEA (0.2 ml, 1.2 mmol) in 3 ml of DMF which was stirred at roomtemperature overnight. The reaction was diluted with ethyl acetate andwashed with cold 1N HCl, saturated sodium bicarbonate and brine. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedusing a 10 g silica gel column eluting with 10% ethyl acetate/n-heptaneto 80% ethyl acetate/n-heptane to give 79.4 mg (46%) of product 3.Compound 3 (73 mg, 0.13 mmol) was then dissolved in 1 ml of methylenechloride and Dess-Martin periodinane (15% in methylene chloride, 0.7358g) was added and the reaction was allowed to at room temperature for 3hours and excess Dess-Martin reagent was consumed by adding sodiumthiosulfate in saturated sodium bicarbonate. The product was extractedwith ethyl acetate and the organic layer was dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The productwas purified using a 10 g silica gel column eluting with 100% n-heptaneto 30% n-heptane/ethyl acetate to yield 32.2 mg (44%) of the finalcompound 4; LCMS retention time 3:57 minutes, M+1 (568.2).

Example 49N-(1,1-Dimethyl-2-oxazol-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

Compound 105 was synthesized according to the following reactionprotocol:

Compound 1 (0.1066 g, 0.3 mmol) and compound 2 (0.0572 g, 0.3 mmol) weremixed with EDC (0.0633 g, 0.33 mmol), HOBT (0.0446 g, 0.33 mmol) andDIEA (0.2 ml, 1.2 mmol) in 3 ml of DMF which was stirred at roomtemperature overnight. The reaction was diluted with ethyl acetate andwashed with cold 1N HCl, saturated sodium bicarbonate and brine. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedusing a 10 g silica gel column eluting with 10% ethyl acetate/n-heptaneto 80% ethyl acetate/n-heptane to give 15 mg (10%) of final product 3;LCMS retention time 3:10 minutes, M+1 (492.2).

Example 50N-4-Isopropyl-N-1-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-2-benzylsulfonylmethyl-succinamide

Compound 106 was synthesized according to the following reactionprotocol:

To a stirring suspension of N-Cyclohexylcarbodiimide, N′-methylpolystyrene resin (1.7 mmole/gram, 0.3529 g, 0.6 mmol) in 10 ml ofmethylene chloride was added the acid 1 (98.2 mg, 0.3 mmol) and HOBT (69mg, 0.51 mmol) which was allowed to stir for 15 minutes at roomtemperature. Compound 2 (80.6 mg, 0.3 mmol) and DIEA (0.1 ml, 0.5 mmol)were added and the reaction was allowed to stir for 5 hours at roomtemperature. Then silicycle triamine™ (0.42 g, 1.5 mmol) was added andthe reaction was stirred overnight at room temperature. The reaction wasfiltered and the solvent was removed under reduced pressure. The crudeproduct 3 was used without further purification. Crude compound 3 wasdissolved in methylene chloride and Dess-Martin reagent (15% inmethylene chloride, 1.13 g, 0.6 mmol) was added and the reaction wasallowed to stir at room temperature for 3 hours. The excess Dess-Martinreagent was consumed by adding sodium thiosulfate in saturated sodiumbicarbonate. The product was extracted with ethyl acetate and washedwith brine. The organic layer was dried over magnesium sulfate, filteredand concentrated under reduced pressure. The product was purified usingHPLC to yield 15 mg of final compound 4; LCMS retention time 3:07minutes, M+1(540.2).

Example 512-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide

Compound 107 was synthesized according to the following reactionprotocol:

To a stirring suspension of N-Cyclohexylcarbodiimide, N′-methylpolystyrene resin (1.7 mmole/gram, 0.2353 g, 0.4 mmol) in 10 ml ofmethylene chloride was added the acid 1 (84.3 mg, 0.2 mmol) and HOBT(45.9 mg, 0.34 mmol) which was allowed to stir for 15 minutes at roomtemperature. Compound 2 (53.75 mg, 0.2 mmol) and DIEA (0.068 ml, 0.4mmol) were added and the reaction was allowed to stir for 5 hours atroom temperature. Then silicycle triamine™ (0.28 g, 1.0 mmol) was addedand the reaction was stirred overnight at room temperature. The reactionwas filtered and the solvent was removed under reduced pressure. Thecrude product 3 was used without further purification. Crude compound 3was dissolved in methylene chloride and Dess-Martin reagent (15% inmethylene chloride, 1.13 g, 0.6 mmol) was added and the reaction wasallowed to stir at room temperature for 3 hours. The excess Dess-Martinreagent was consumed by adding sodium thiosulfate in saturated sodiumbicarbonate. The product was extracted with ethyl acetate and washedwith brine. The organic layer was dried over magnesium sulfate, filteredand concentrated under reduced pressure. The product was purified usingHPLC to yield 6 mg of final compound 4; LCMS retention time 3:09minutes, M+1 (634.4).

Example 522-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide

Compound 108 was synthesized according to the following reactionprotocol:

To a stirring suspension of N-Cyclohexylcarbodiimide, N′-methylpolystyrene resin (1.7 mmole/gram, 0.2353 g, 0.4 mmol) in 10 ml ofmethylene chloride was added the acid 1 (64.3 mg, 0.2 mmol) and HOBT(45.9 mg, 0.34 mmol) which was allowed to stir for 15 minutes at roomtemperature. Compound 2 (53.75 mg, 0.2 mmol) and DIEA (0.068 ml, 0.4mmol) were added and the reaction was allowed to stir for 5 hours atroom temperature. Then silicycle triamine™ (0.28 g, 1.0 mmol) was addedand the reaction was stirred overnight at room temperature. The reactionwas filtered and the solvent was removed under reduced pressure. Thecrude product 3 was used without further purification. Crude compound 3was dissolved in methylene chloride and Dess-Martin reagent (15% inmethylene chloride, 1.13 g, 0.6 mmol) was added and the reaction wasallowed to stir at room temperature for 3 hours. The excess Dess-Martinreagent was consumed by adding sodium thiosulfate in saturated sodiumbicarbonate. The product was extracted with ethyl acetate and washedwith brine. The organic layer was dried over magnesium sulfate, filteredand concentrated under reduced pressure. The product was purified usingHPLC to yield 25.7 mg of final compound 4; LCMS retention time 2:89minutes, M+1(534.4).

Example 532-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide

Compound 109 was synthesized according to the following reactionprotocol:

To a stirring suspension of N-Cyclohexylcarbodiimide, N′-methylpolystyrene resin (1.7 mmole/gram, 0.2353 g, 0.4 mmol) in 10 ml ofmethylene chloride was added the acid 1 (63.9 mg, 0.2 mmol) and HOBT(45.9 mg, 0.34 mmol) which was allowed to stir for 15 minutes at roomtemperature. Compound 2 (53.75 mg, 0.2 mmol) and DIEA (0.068 ml, 0.4mmol) were added and the reaction was allowed to stir for 5 hours atroom temperature. Then silicycle triamine™ (0.28 g, 1.0 mmol) was addedand the reaction was stirred overnight at room temperature. The reactionwas filtered and the solvent was removed under reduced pressure. Thecrude product 3 was used without further purification. Crude compound 3was dissolved in methylene chloride and Dess-Martin reagent (15% inmethylene chloride, 1.13 g, 0.6 mmol) was added and the reaction wasallowed to stir at room temperature for 3 hours. The excess Dess-Martinreagent was consumed by adding sodium thiosulfate in saturated sodiumbicarbonate. The product was extracted with ethyl acetate and washedwith brine. The organic layer was dried over magnesium sulfate, filteredand concentrated under reduced pressure. The product was purified usingHPLC to yield 11.6 mg of final compound 4; LCMS retention time 2:77minutes, M+1 (532.4).

Example 54N-[1-(Benzooxazole-2-carbonyl)-butyl]-2-benzylsulfonyl-3-(tetrahydro-pyran-4-yloxymethyl)-propionamide

Diisopropylethylamine (0.184 ml, 1.05 mmol) was added to a mixture of3-benzylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (362mg, 1.05 mmol), prepared as in reference 27, and2-amino-1-benzooxazol-2-yl-pentan-1-ol (238 mg, 1.05 mmol) and HATU (402mg, 1.05 mmol) in DMF (10 ml) and stirred at room temperature overnight.Solvent was evaporated under reduced pressure, crude extract was takenup in ethyl acetate (30 ml) and washed with 1N HCl, saturated NaHCO₃ andbrine. After drying over MgSO₄ the solvent was removed by rotaryevaporation and the residue chromatographed on silica eluting with ethylacetate/heptane mixture to giveN—[(S)-1-(benzoxazol-2-yl-hydroxy-methyl)-butyl]-2-benzylsulfonylmethyl-3-(tetrahydro-pyran-4-yloxy)-propionamide(Yield: 258 mg); MS: 545 (M+1); LCMS retention time 3.71 and 3.76minutes.

A solution ofN—[(S)-1-(benzoxazol-2-yl-hydroxy-methyl)-butyl]-2-benzylsulfonylmethyl-3-(tetrahydro-pyran-4-yloxy)-propionamide(243 mg, 0.45 mmol) methylene chloride (8 ml) was treated withDess-Martin periodinane (190 mg, 0.45 mmol) at room temperature for 2hours. Washed with 0.26M solution of Na₂S₂O₃, NaHCO₃ and brine. Afterdrying over MgSO₄ the solvent was removed by rotary evaporation and theresidue chromatographed on silica eluting with ethyl acetate/heptanemixture to giveN-[1-(benzooxazole-2-carbonyl)-butyl]-2-benzylsulfonyl-3-(tetrahydro-pyran-4-yloxymethyl)-propionamideas off white solid (Yield: 60 mg); MS: 543 (M+1); LCMS retention time4.1 minutes.

Example 55N-[1-(Benzooxazole-2-carbonyl)-butyl-3-ethanesulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide

By following the method for Example 54 but substituting the requiredcarboxylic acid with3-ethylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid, asprepared in reference 27b,N-[1-(benzooxazole-2-carbonyl)-butyl]-3-ethanesulfonyl-2-(tetrahydropyran-4-yloxymethyl)-propionamidewas prepared. MS: 481 (M+1); LCMS retention time 3.7 minutes.

Example 56N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyramide

Compound 112 was prepared by the following protocol. The circlesymbolizes the polystyrene backbone while the square symbolizes thesilicium dioxide backbone:

1.16 mol-equivalents of the acid were dissolved in dichloromethyl.N-Cyclohexylcarbodiimide, N′-methylpolystyrene (2 mol-equivalents) andhydroxybenzotriazole (1.72 mol-equivalents) were added and the resultingreaction mixture stirred for 10 minutes.4-Amino-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester (1mol-equivalent) was added and stirring continued for 21 hours.Silicycle-Triamine-3™ was added and the resulting mixture stirred forsix hours. The mixture was filtered under suction and the filtrateconcentrated under vacuum.

The alcohol was dissolved in dichloromethyl and 2 mol-equivalents ofDess-Martin periodinane were added to the solution. The reaction mixturewas stirred for one hour. Equal volumes of saturated sodium thiosulfatesolution and sat sodium bicarbonate solution were added and the phasesseparated. The aqueous phase was extracted three times withdichloromethyl. The combined organic phases were washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution. Thesolution was dried with magnesium sulfate and the solvents evaporated.

The azepanone-1-carboxylic acid tert-butyl ester was dissolved in adichloromethyl solution (20 vol-%) of trifluoroacetic acid. Afterstirring for one hour dichloromethyl was removed under reduced pressureand trifluoroacetic acid under high vacuum. The solid residue wasre-dissolved in dichloromethyl and five mol-equivalent of triethylaminewere added. 1.2 mol-equivalent of benzenesulfonyl chloride were addedand the reaction mixture stirred for four hours. 12 mol-equivalents ofSilicycle Triamine™ were added and stirring continued for two hours. Themixture was filtered under suction and the dichloromethyl evaporatedunder reduced pressure. The crude product was purified via preparativeHPLC yieldingN-(1-benzenesulfonyl-3-oxo-azepan-4-yl)-2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyramideas an off-white solid; LC/MS retention time 2.61 minutes, m/z=570 (M+H).

The following examples were prepared according to methods described inExample 56:

2-Cyclopropylmethylsulfonylmethyl-N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl)-4-morpholin-4-yl-4-oxo-butyramide

Tan solid; LC/MS retention time 3.456 minutes (TIC), m/z=557 (M+Na).

N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-2-(2-methylpropane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide

Tan solid; LC/MS retention time 3.594 minutes (TIC), m/z=559 (M+Na).

2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-amide

Tan solid; LC/MS retention time 3.379 minutes (TIC), m/z=521 (M+H).

2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide

Tan solid; LC/MS retention time 2.976 minutes (TIC), m/z=533 (M+H).

2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide

Tan solid; LC/MS retention time 3.433 minutes (TIC), m/z=535 (M+H).

2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid,(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide

Tan solid; LC/MS retention time 3.762 minutes (TIC), m/z=519 (M+H).

Example 573-Hydroxy-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butylamino)-azepane-1-carboxylicacid tert-butyl ester

Tan solid prepared according to example 56; LC/MS retention time 2.985minutes (TIC), m/z=568 (M+H) and 590 (M+Na).

Example 584-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-hydroxy-azepane-1-carboxylicacid tert-butyl ester

Tan solid prepared according example 56; LC/MS retention time 2.786minutes (TIC), m/z=532 (M+H) and 554 (M+Na).

Example 593-Hydroxy-4-[2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-azepane-1-carboxylicacid tert-butyl ester

Tan solid prepared according example 56; LC/MS retention time 2.903minutes (TIC), m/z=534 (M+H).

Example 604-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylicacid tert-butyl ester

Tan solid prepared according example 56; LC/MS retention time 3.163minutes (TIC), m/z=566 (M+H).

Example 614-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-oxo-azepane-1-carboxylicacid tert-butyl ester

Tan solid prepared according to example 56; LC/MS retention time 2.965minutes (TIC), m/z=530 (M+H).

Example 624-[2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-3-oxo-azepane-1-carboxylicacid tert-butyl ester

Tan solid prepared according to example 56; LC/MS retention time 3.083minutes (TIC), m/z=532 (M+H).

Example 63N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

Off-white solid prepared according example 56; LC/MS retention time 2.83minutes (TIC), m/z=606 (M+H).

Example 64N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide

Off-white solid prepared according example 56; LC/MS retention time 2.72minutes (TIC), m/z=572 (M+H).

Example 65N-[(1S)-1-(Benzooxazol-2-yl-hydroxy-methyl)-3-phenyl-propyl]-2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyramide

Compound 121 was prepared according to the following reaction scheme:

0.25 mmol (1.16 mol-equivalent) of2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acidwas dissolved in 10 ml dichloromethyl. 252 mg, 0.43 mmolN′-cyclohexylcarbodiimide, N-methylpolystyrene (2 mol-equivalents) and50 mg, 0.37 mmol hydroxybenzotriazole (1.72 mol-equivalents) were addedand the resulting reaction mixture stirred for 10 minutes. 61 mg, 0.215mmol 2-amino-1-benzooxazol-2-yl-4-phenyl-butan-1-ol (1 mol-equivalents)was added and stirring continued for 21 hours. 510 mg, 2.15 mmolSilicycle-Triamine-3™ was added and the resulting mixture stirred for 6hours. The mixture was filtered under suction and the filtrateconcentrated under vacuum yielding 83 mg, 0.142 mmol (66%) ofN-[(1S)-1-(Benzooxazol-2-yl-hydroxy-methyl)-3-phenyl-propyl]-2-cyclopropylmethylsulfonyl-0methyl-4-morpholin-4-yl-4-oxo-butyramideas a tan solid; LC/MS retention time 3.256 min (TIC), m/z=584 (M+H).

Example 66(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid, 1-(benzoxazole-2-carbonyl)-propyl]-amide

PyBOP (126 mg, 0.24 mmol), DIPEA (0.096 ml, 0.55 mmol) and2-Amino-1-benzooxazol-2-yl-butan-1-one hydrochloride (53 mg, 0.22 mmol)were added to a solution of(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoicacid (70.7 mg, 0.22 mmol) in dry methylene chloride (5 ml) and thereaction mixture was stirred overnight at room temperature. The reactionwas concentrated under reduced pressure, the residue dissolved in ethylacetate and washed with water. Organic extract was dried over MgSO₄ andevaporated under reduced pressure. Column chromatography on silicaeluting with a mixture of ethyl acetate and heptane gave the titlecompound as white solid (38 mg); ¹H NMR (CDCl₃) δ 1.02 (t, J=7.4 Hz,3H), 1.97-1.62 (m, 5H), 2.21-2.15 (m, 1H), 2.74-2.59 (m, 3H), 3.65-3.49(m, 8H), 4.41 (m, 1H), 4.70 (m, 1H), 5.62 (m, 1H), 6.93 (d, J=7.1 Hz)6.68 (d, J=7.1 Hz, 1H), 7.33-7.13 (m, 5H), 7.49 (t, J=8 Hz, 1H), 7.57(t, J=8 Hz, 1H), 7.66 (d, J=5.9, 1H), 7.92 (d, J=8 Hz, 1H); MS:508(MH⁺); LC/MS retention time was 3.05 minutes.

Example 67(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid, 1-(benzoxazole-2-carbonyl)-propyl]-amide

Similarly prepared according to the procedure in Example 66 but using(R)-5-(2-difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoicacid as the acidic component; ¹H NMR (CDCl₃) δ 1.06 (t, J=7.5 Hz, 3H),1.97-1.63 (m, 5H), 2.23-2.14 (m, 1H), 2.79-2.68 (m, 3H), 3.75-3.50 (m,8H), 4.42 (m, if H), 4.81-4.62 (m, 1H), 5.61 (m, 1H), 6.53 (t, J=74 Hz,1H), 6.73 (d, J=7.1 Hz), 6.98 (d, J=7.1 Hz, 1H), 7.24-7.06 (m, 4H),7.59-7.49 (m, 2H), 7.69-7.64 (m, 1H), 7.91 (d, J=7.9 Hz, 1H); MS:574(MH⁺).

Example 684-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-cyclopropyl]-4-oxo-2-benzylsulfonylmethyl-butyramide

Similarly prepared according to the procedure in Example 66 but using4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid as the acidiccomponent and (1-Amino-cyclopropyl)-oxazol-2-yl-methanone hydrochlorideas the basic component; MS: 490 (MH⁺); LC/MS, retention time 2.44minutes.

Example 69 Cathepsin S Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100mM). Human cathepsin S(0.158 pMoles in 25 μL of assay buffer) was addedto the dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 minutes at ambienttemperature. Z-Val-Val-Arg-AMC (9 nMoles in 25 μL of assay buffer) wasadded to the assay solutions and hydrolysis was followedspectrophotometrically at (λ 460 nm) for 5 minutes. Apparent inhibitionconstants (K_(i)) were calculated from the enzyme progress curves usingstandard mathematical models.

Example 70 Cathepsin B Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid(BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; anddithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μLof assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30minutes at ambient temperature. Z-FR-AMC (20 nMoles in 25 μL of assaybuffer) was added to the assay solutions and hydrolysis was followedspectrophotometrically at (λ 460 nm) for 5 minutes. Apparent inhibitionconstants (K_(i)) were calculated from the enzyme progress curves usingstandard mathematical models.

Example 71 Cathepsin K Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).Human cathepsin K (0.0906 pMoles in 25 μL of assay buffer) was added tothe dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 minutes at ambienttemperature. Z-Phe-Arg-AMC (4 nMoles in 25 μL of assay buffer) was addedto the assay solutions and hydrolysis was followedspectrophotometrically at (λ 460 nm) for 5 minutes. Apparent inhibitionconstants (K_(i)) were calculated from the enzyme progress curves usingstandard mathematical models.

Example 72 Cathepsin L Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).Human cathepsin L (0.05 pMoles in 25 μL of assay buffer) was added tothe dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 minutes at ambienttemperature. Z-Phe-Arg-AMC (1 nMoles in 25 μL of assay buffer) was addedto the assay solutions and hydrolysis was followedspectrophotometrically at (λ 460 nm) for 5 minutes. Apparent inhibitionconstants (K_(i)) were calculated from the enzyme progress curves usingstandard mathematical models.

Compounds of the invention were tested according to the above-describedassays for protease inhibition and observed to exhibit selectivecathepsin S inhibitory activity. For example, the compounds of theinvention were found to inhibit cathepsin S protease activity atconcentrations that are least 50 fold less than those concentrationsrequired to produce an equiactive inhibition of cathepsin K proteaseactivity. The apparent inhibition constants (K_(i)) for compounds of theinvention, against Cathepsin S, were in the range from about 10⁻¹⁰M toabout 10⁻⁷M.

Example 73 Representative Pharmaceutical Formulations Containing aCompound of Formula I

ORAL FORMULATION Compound of Formula I 10-100 mg Citric Acid Monohydrate105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL INTRAVENOUSFORMULATION Compound of Formula I 0.1-10 mg Dextrose Monohydrate q.s. tomake isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mgWater for Injection q.s. to 1.0 mL TABLET FORMULATION Compound ofFormula I  1% Microcrystalline Cellulose 73% Stearic Acid 25% ColloidalSilica   1%.

LENGTHY TABLE The patent application contains a lengthy table section. Acopy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070049594A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of Formula I:

in which: X¹ is —C(R¹)(R²)X² or —X³; X² is cyano, —CHO, —C(R⁷)(R⁸)R⁵, —C(R⁷)(R⁸)CF₃, —C(R⁷)(R⁸)CF₂CF₂R⁹—CH═CHS(O)₂R⁵, —C(R⁷)(R⁸)CF₂C(O)NR⁵R⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)NR⁵R⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)OR⁵, —C(R⁷)(R⁸)CH₂OR⁵, —C(R⁷)(R⁸)CH₂N(R⁶)SO₂R⁵, —C(R⁷)(R⁸)C(R⁷)(R⁸)N(R⁶)(CH₂)₂OR⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)N(R⁶)(CH₂)₂NR⁶ or —C(R⁷)(R⁸)C(R⁷)(R⁸)R⁵; wherein R⁵ is (C₁₋₄)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₄₋₁₀)aryl(C₀₋₆)alkyl, (C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl or hetero(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl; R⁶ is hydrogen or (C₁₋₆)alkyl; R⁷ is hydrogen or (C₁₋₄)alkyl and R⁸ is hydroxy or R⁷ and R⁸ together form oxo; R⁹ is hydrogen, halo, (C₁₋₄)alkyl, (C₅₋₁₀)aryl(C₀₋₆)alkyl or hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl; X³ represents a group of Formula (a):

in which n is 1 or 2, z is 0 or 1, X⁵ is selected from NR¹⁰, S or O, wherein R¹⁰ is hydrogen or (C₁₋₆)alkyl, and X⁶ is O, S or NR¹¹, wherein R¹¹ is selected from hydrogen, (C₁₋₆)alkyl, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵ and —X⁴S(O)₂NR¹²R¹⁵, in which X⁴ is a bond or (C₁₋₆)alkylene; R¹² at each occurrence independently is hydrogen or (C₁₋₆)alkyl; R¹³ is hydrogen, (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl; wherein within X¹ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R²⁰ selected from —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹²; and wherein X¹ and R²⁰ may be substituted further with 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴ wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; R¹ and R² are both fluoro; or R¹ is hydrogen or (C₁₋₆)alkyl and R² is selected from the group consisting of hydrogen, (C₁₋₆)alkyl, cyano, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴, —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; or R¹ and R² taken together with the carbon atom to which both R¹ and R² are attached form (C₃₋₈)cycloalkylene or hetero(C₃₋₈)cycloalkylene; wherein R², said cycloalkylene and said heterocycloalkylene may be substituted further with 1 to 3 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴ SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above; R³ and R⁴ are independently —C(R¹⁶)(R¹⁷)X⁷, wherein R¹⁶ and R¹⁷ are hydrogen, (C₁₋₆)alkyl or fluoro, or R¹⁶ is hydrogen and R¹⁷ is hydroxy and X⁷ is selected from —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴, —X⁴S(O)₂R¹⁴, —R¹⁵, X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; wherein within one of R³ or R⁴ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R²¹ selected from —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵, —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹² and R¹⁵ are as defined above; and wherein each of R³, R⁴ and R²¹ may be substituted further with 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above; provided that only one bicyclic ring structure is present within each of R³ or R⁴; and provided that when X² is cyano and X⁷ within one of R³ or R⁴ is —X⁴C(O)R¹³ or —X⁴C(O)R¹⁵, wherein X⁴ is a bond, then X⁷ within the other of R³ or R⁴ is limited to —X⁴SR¹⁵, —X⁴S(O)R¹⁵ and —X⁴S(O)₂R¹⁵, wherein R¹⁵ is (C₆₋₁₀)aryl(C₁₋₆)alkyl substituted with 1 to 5 radicals or hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl optionally substituted with 1 to 5 radicals, wherein said radicals are independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above, provided that the radical is not selected from only halo when R¹⁵ is (C₆₋₁₀)aryl(C₁₋₆)alkyl; and provided that when X² is cyano then X⁷ within R³ and R⁴ is not —X⁴C(O)NR¹²R¹², —X⁴C(O)NR¹⁵R¹² or —X⁴C(O)NR¹⁸R¹⁹, wherein X⁴ is a bond and R¹⁸ and R¹⁹ together with the nitrogen atom to which they are attached form hetero(C₃₋₁₀)cycloalkyl or hetero(C₅₋₁₀)aryl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 2. The compound of claim 1 in which: X¹ is —C(R¹)(R²)X² or —X³; X² is cyano, —CHO, —C(O)R⁵, —C(O)CF₃, —C(O)CF₂CF₂R⁹—CH═CHS(O)₂R⁵, —C(O)CF₂C(O)NR⁵R⁶, —C(O)C(O)NR⁵R⁶, —C(O)C(O)OR⁵, —C(O)CH₂OR⁵, —C(O)CH₂N(R⁶)SO₂R⁵, —C(O)C(O)N(R⁶)(CH₂)₂OR⁶, —C(O)C(O)N(R⁶)(CH₂)₂NR⁶ or —C(O)C(O)R⁵, wherein R⁵ is (C₁₋₄)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₄₋₁₀)aryl(C₀₋₆)alkyl, (C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl or hetero(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl, R⁶ is hydrogen or (C₁₋₆)alkyl and R⁹ is halo; X³ represents a group of Formula (b):

in which n is 1 or 2, z is 0 or 1, X⁶ is O or NR¹¹, wherein R¹¹ is selected from hydrogen, (C₁₋₆)alkyl, —X⁴OC(O)R¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵ and —X⁴S(O)₂NR¹²R¹⁵, in which X⁴ is a bond or (C₁₋₆)alkylene; R¹² at each occurrence independently is hydrogen or (C₁₋₆)alkyl; R¹³ is hydrogen, (C₁₋₄)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl; wherein within X¹ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R¹⁵ and —X⁴C(O)R¹⁵; and wherein X¹ may be substituted further with 1 to 3 radicals independently selected from (C₁₋₆)alkyl, halo-substituted(C₁₋₄)alkyl, —X⁴NR¹²R¹², —X⁴OR¹³ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; R¹ and R² are both fluoro; or R¹ is hydrogen or (C₁₋₆)alkyl and R² is selected from the group consisting of hydrogen, (C₁₋₆)alkyl, —X⁴OR¹³ and —R¹⁵; or R¹ and R² taken together with the carbon atom to which both R¹ and R² are attached form (C₃₋₈)cycloalkylene or hetero(C₃₋₈)cycloalkylene; wherein R² may be substituted further with (C₁₋₆)alkyl; wherein X⁴, R¹³ and R¹⁵ are as defined above; R³ and R⁴ are independently —C(R¹⁶)(R¹⁷)X⁷, wherein R¹⁶ and R¹⁷ are hydrogen, (C₁₋₆)alkyl or fluoro, or R¹⁶ is hydrogen and R¹⁷ is hydroxy and X⁷ is selected from —X⁴SR¹³, —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵ and —X⁴C(O)NR¹⁵R¹², wherein X⁴, R¹², R¹³ and R¹⁵ are as defined above; wherein within one of R³ or R⁴ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵, —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹² and R¹⁵ are as defined above; and wherein each of R³ and R⁴ may be substituted further with 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above; wherein within one of R³ and R⁴ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R¹⁵ and —X⁴OR¹⁵; and wherein each of R³ or R⁴ may be substituted further by 1-5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, —X⁴NR¹²C(O)OR¹², —X⁴OR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴NR¹²S(O)₂R¹³ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 3. A compound of claim 2 in which R³ and R⁴ are independently —CH₂X⁷, wherein X⁷ is selected from X⁴SR¹³, —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵ and —X⁴C(O)NR¹⁵R¹², wherein X⁴ is a bond or (C₁₋₆)alkylene, R¹² at each occurrence independently is hydrogen or (C₁₋₆)alkyl, R¹³ is hydrogen, (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl; wherein within R³ and R⁴ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical selected from —R¹⁵ and —X⁴OR¹⁵, wherein X⁴ and R¹⁵ are as defined above; and wherein R³ and R⁴ may be substituted further by 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, —X⁴NR¹²C(O)OR¹², —X⁴OR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴NR¹²S(O)₂R¹³ and —X⁴S(O)₂R¹⁴, wherein X⁴R¹², R¹³ and R¹⁴ are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 4. A compound of claim 3 in which R³ is selected from 5-bromo-thiophen-2-ylmethyl, 3-cyclohexylpropyl, 2-cyclohexylpropyl, 2-cyclopentylpropyl, 3-phenylpropyl, 3-(2-difluoromethoxy)phenylpropyl, 2-phenylcyclopropylmethyl, 2,2-difluoro-3-phenylpropyl, 1-benzylcyclopropylmethy, 2-tetrahydro-pyran-4-ylethyl, 1-isobutylcyclopropylmethyl, thiophen-2-ylmethyl, tetrahydro-pyran-4-ylmethyl, cyclopropylmethylsulfanylmethyl, 2,2-dimethyl-3-phenylpropyl, 4-methyl-[[1,2,5]thiadiazol-3-ylmethylsulfonylmethyl, 3-methyl-[1,2,4]thiadiazol-3-ylmethylsulfonylmethyl, thiophen-3-ylmethylsulfonylmethyl, 3-methoxy-5-methyl-isoxazol-4-ylmethylsulfonylmethyl, 2,4-dimethyl-thiazol-5-ylmethylsulfonylmethyl, 2-methyl-oxazol-4-ylmethylsulfonylmethyl, 2-methyl-thiazol-4-ylmethylsulfonylmethyl, [1,2,3]thiadiazol-4-ylmethylsulfonylmethyl, 3-methyl-[1,2,4]thiadiazol-5-ylmethylsulfonylmethyl, 4-methyl-[1,2,5]thiadiazol-3-ylmethylsulfonylmethyl, thiophen-3-ylmethylsulfonylmethyl, tetrahydro-pyran-4-yloxymethyl, piperidin-1-ylcarbonyl, thiophene-2-sulfonylmethyl, 3-chloro-2-fluoro-benzylsulfonylmethyl, benzenesulfonylmethyl, benzylsulfonylmethyl, 2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl, 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl, 2-benzylsulfonyl-ethyl, oxy-pyridin-2-ylmethylsulfonylmethyl, prop-2-ene-1-sulfonylmethyl, 4-methoxy-benzylsulfonylmethyl, p-tolylmethylsulfonylmethyl, 4-chloro-benzylsulfonylmethyl, o-tolylmethylsulfonylmethyl, 3,5-dimethyl-benzylsulfonylmethyl, 4-trifluoromethyl-benzylsulfonylmethyl, 4-trifluoromethoxy-benzylsulfonylmethyl, 2-bromo-benzylsulfonylmethyl, pyridin-2-ylmethylsulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl, pyridin-4-ylmethylsulfonylmethyl, naphthalen-2-ylmethylsulfonylmethyl, 3-methyl-benzylsulfonylmethyl, 3-trifluoromethyl-benzylsulfonylmethyl, 3-trifluoromethoxy-benzylsulfonylmethyl, 4-fluoro-2-trifluoromethoxy-benzylsulfonylmethyl, 2-fluoro-6-trifluoromethyl-benzylsulfonylmethyl, 3-chloro-benzylsulfonylmethyl, 2-fluoro-benzylsulfonylmethyl, 2-trifluoro-benzylsulfonylmethyl, 2-cyano-benzylsulfonylmethyl, 4-tert-butyl-benzylsulfonylmethyl, 2-fluoro-3-methyl-benzylsulfonylmethyl, 3-fluoro-benzylsulfonylmethyl, 4-fluoro-benzylsulfonylmethyl, 2-chloro-benzylsulfonylmethyl, 2,5-difluoro-benzylsulfonylmethyl, 2,6-difluoro-benzylsulfonylmethyl, 2,5-dichloro-benzylsulfonylmethyl, 3,4-dichloro-benzylsulfonylmethyl, 2-(11,1-difluoro-methoxy)-benzylsulfonylmethyl, 2-cyano-benzylsulfonylmethyl, 3-cyano-benzylsulfonylmethyl, 2-trifluoromethoxy-benzylsulfonylmethyl, 2,3-difluoro-benzylsulfonylmethyl, 2,5-difluoro-benzylsulfonylmethyl, biphenyl-2-ylmethylsulfonylmethyl, cyclohexylmethyl, 3-fluoro-benzylsulfonylmethyl, 3,4-difluoro-benzylsulfonylmethyl, 2,4-difluoro-benzylsulfonylmethyl, 2,4,6-trifluoro-benzylsulfonylmethyl, 2,4,5-trifluoro-benzylsulfonylmethyl, 2,3,4-trifluoro-benzylsulfonylmethyl, 2,3,5-trifluoro-benzylsulfonylmethyl, 2,5,6-trifluoro-benzylsulfonylmethyl, 2-chloro-5-trifluoromethylbenzylsulfonylmethyl, 2-methyl-propane-1-sulfonyl, 2-fluoro-3-trifluoromethylbenzylsulfonylmethyl, 2-fluoro-4-trifluoromethylbenzylsulfonylmethyl, 2-fluoro-5-trifluoromethylbenzylsulfonylmethyl, 4-fluoro-3-trifluoromethylbenzylsulfonylmethyl, 2-methoxy-benzylsulfonylmethyl, 3,5-bis-trifluoromethyl-benzylsulfonylmethyl, 4-difluoromethoxy-benzylsulfonylmethyl, 2-difluoromethoxy-benzylsulfonylmethyl, 3-difluoromethoxy-benzylsulfonylmethyl, 2,6-dichloro-benzylsulfonylmethyl, biphenyl-4-ylmethylsulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethylsulfonylmethyl, 5-chloro-thiophen-2-ylmethylsulfonylmethyl, 2-[4-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[2-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[3-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl, (cyanomethyl-methyl-carbamoyl)-methyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethylsulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, phenylsulfanyl-ethyl and cyclopropylmethylsulfonylmethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 5. A compound of claim 4 in which R⁴ is selected from 2-trifluorobenzylsulfonylmethyl, 3-phenylsulfanylpropyl, 4-chlorobenzylsulfonylmethyl, thiophen-2-ylsulfonylmethyl, benzylsulfonylmethyl, 4-methylbenzylsulfonylmethyl, 2-phenylsulfonylethyl, 2-pyridin-2-ylsulfonylethyl, 2-pyridin-4-ylsulfonylethyl, 2-benzylsulfonylethyl, 2-(3-difluoromethoxyphenylsulfonyl)ethyl, naphthalen-2-ylmethylsulfonylmethyl, pyridin-2-ylmethylsulfonylmethyl, 3-methylbenzylsulfonylmethyl, 3-trifluoromethylbenzylsulfonylmethyl, 3-difluoromethoxybenzylsulfonylmethyl, 3-chlorobenzylsulfonylmethyl, 3-fluorobenzylsulfonylmethyl, 4-fluorobenzylsulfonylmethyl, 3-cyanobenzylsulfonylmethyl, 4-cyanobenzylsulfonylmethyl, 3,4-difluorobenzylsulfonylmethyl, benzylsulfonylmethyl, N-cyanomethyl-N-methylcarbamoylmethyl, 3-bromobenzyl, 4-phenylbutyl, 2,2-difluoro-3-phenylpropyl, 4′-methylsulfonylaminobiphenyl-3-ylmethyl, 4′-ethoxycarbonylaminobiphenyl-3-ylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl, 1-fluoro-2-(4-methylpiperazin-1-yl)-2-oxoethyl, 1-hydroxy-4-methylpiperazin-1-yl-2-oxoethyl, 1-hydroxy-2-morpholin-4-yl-2-oxoethyl, 1-hydroxy-2-oxo-2-pyrrolidin-1-yl-ethyl, 1-fluoro-2-oxo-2-pyrrolidin-1-yl-ethyl, 1-fluoro-2-isopropylamino-2-oxoethyl, 1-hydroxy-2-isopropylamino-2-oxoethyl, 1-fluoro-2-oxo-2-piperazin-1-ylethyl, thiophen-3-ylmethylsulfonylmethyl, 4-methyl-[1,2,5]thiadiazol-3-ylmethylsulfonylmethyl, 3-methoxy-5-methyl-isoxazol-4-ylmethylsulfonylmethyl, 2,4-dimethyl-thiazol-5-ylmethylsulfonylmethyl, 2-methyl-oxazol-4-ylmethylsulfonylmethyl, 2-methyl-thiazol-4-ylmethylsulfonylmethyl, 2-([1,2,3]thiadiazol-4-ylmethylsulfonyl)-ethyl, 2-(3-methyl-[1,2,4]thiadiazol-5-ylmethylsulfonyl)-ethyl, 2-oxo-2-phenyl-ethyl, 2-morpholin-4-yl-2-oxo-ethyl, 2-benzenesulfonyl-ethyl, 2-naphthalen-2-yl-2-oxo-ethyl, 2-benzo[1,3]dioxol-5-yl-2-oxo-ethyl, 2-benzo[b]thiophen-2-yl-2-oxo-ethyl, 2-biphenyl-4-yl-2-oxo-ethyl, 4-benzylsulfonylmethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-oxo-2-(4-phenoxy-phenyl)-ethyl, 2-(4-hydroxy-phenyl)-2-oxo-ethyl, benzylcarbamoyl-methyl, 4-acetyl-piperazine-1-carboxylic acid ethyl ester, cyclohexylcarbamoylmethyl, 2-(3-Chloro-benzo[b]thiophen-2-yl)-2-oxo-ethyl, benzenesulfonylmethyl, 2-oxo-2-thiophen-2-yl-ethyl, 2-oxo-2-thiophen-3-yl-ethyl, naphthalene-2-sulfonylmethyl, 2-(5-methyl-thiophen-2-yl)-2-oxo-ethyl, 2-(3-chloro-thiophen-2-yl)-2-oxo-ethyl, 5-methyl-thiophene-2-sulfonylmethyl, phenylcarbamoylmethyl, (5,6,7,8-tetrahydro-naphthalen-1-ylcarbamoyl)-methyl, (4-carbamoyl-phenylcarbamoyl)-methyl, (3-carbamoyl-phenylcarbamoyl)-methyl, (butyl-methyl-carbamoyl)-methyl, biphenyl-4-ylmethyl, 2-oxo-2-p-tolyl-ethyl, 2-(3-fluoro-4-methoxy-phenyl)-2-oxo-ethyl, 2-(4-chloro-phenyl)-2-oxo-ethyl, 2-(4-methoxy-phenyl)-2-oxo-ethyl, 2-oxo-2-(4-trifluoromethoxy-phenyl)-ethyl, 2-(3,4-difluoro-phenyl)-2-oxo-ethyl, 2-(3,4-dimethoxy-phenyl)-2-oxo-ethyl, 2-(4-fluoro-phenyl)-2-oxo-ethyl, 5-methyl-2-oxo-hexyl, 3,5-dimethyl-benzylsulfonylmethyl, 4-trifluoromethyl-benzylsulfonylmethyl; 4-trifluoromethoxy-benzylsulfonylmethyl, isopropylcarbamoyl-methyl, 4-dimethylcarbamoylmethyl, pyridin-4-ylcarbamoylmethyl, pyridin-4-ylmethylsulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl, 3,4-dichloro-benzylsulfonylmethyl, pyridin-3-ylcarbamoylmethyl, 4-methoxy-benzylsulfonylmethyl, 4-chloro-benzylsulfonylmethyl, thiophene-2-sulfonylmethyl, benzylsulfonylmethyl, p-tolylmethylsulfonylmethyl, 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl, 2-benzylsulfonyl-ethyl, 2-[3-(11,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, naphthalen-2-ylmethylsulfonylmethyl, pyridin-2-ylmethylsulfonylmethyl, m-tolylmethylsulfonylmethyl, 3-trifluoromethyl-benzylsulfonylmethyl, 3-trifluoromethoxy-benzylsulfonylmethyl, 3-chloro-benzylsulfonylmethyl, 3-fluoro-benzylsulfonylmethyl, 4-fluoro-benzylsulfonylmethyl, 3-cyano-benzylsulfonylmethyl, 4-cyano-benzylsulfonylmethyl, 3,4-difluoro-benzylsulfonylmethyl, (cyanomethyl-methyl-carbamoyl)-methyl, 3-bromo-benzyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-(4′-chloro-biphenyl-4-yl)-2-oxo-ethyl, biphenyl-3-ylmethyl, 2-(11,1-difluoro-methoxy)-benzylsulfonylmethyl, 2-(4-methylsulfonylamino-phenyl)-2-oxo-ethyl, 2-oxo-2-piperidin-1-yl-ethyl, 2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl, 2-trifluoromethyl-benzylsulfonylmethyl, 4-fluoro-3-trifluoromethyl-benzylsulfonylmethyl, 4-carboxy-benzylsulfonylmethyl, 3,5-bis-trifluoromethyl-benzylsulfonylmethyl, 4-(, 1-difluoro-methoxy)-benzylsulfonylmethyl, 3-(1,1-difluoro-methoxy)-benzylsulfonylmethyl, 5-chloro-thiophen-2-ylmethylsulfonylmethyl, 2-[4-(1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-phenylsulfanyl-ethyl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, 2-trifluoromethoxy-benzylsulfanylmethyl, 2-cyclohexyl-ethyl and isobutylsulfanylmethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 6. The compound of claim 5 in which R¹ is hydrogen or (C₁₋₆)alkyl and R² is hydrogen, —X⁴OR¹³, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₅₋₁₀)aryl(C₀₋₆)alkyl or (C₁₋₆)alkyl; or R¹ and R² taken together with the carbon atom to which both R¹ and R² are attached form (C₃₋₈)cycloalkylene or hetero(C₃₋₈)cycloalkylene; wherein the cycloalkylene or heterocycloalkylene are optionally substituted with 1 to 3 (C₁₋₆)alkyl radicals; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 7. The compound of claim 6 in which R¹ is hydrogen or methyl and R² is methoxymethyl, methoxyethyl, methyl, ethyl, propyl, butyl, phenethyl, hiophen-2-yl or 5-methyl-furan-2-yl; or R¹ and R² taken together with the carbon atom to which both R¹ and R² are attached form cyclopropyl, tetrahydro-pyran-4-yl or 1-methyl-piperidin-4-yl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 8. The compound of claim 7 of Formula I(a):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 9. The compound of claim 8 selected from the group consisting of 3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide; 3-biphenyl-4-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide; 3-(3-bromo-phenyl)-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide; N-cyanomethyl-3-(3-cyano-benzylsulfonyl)-2-benzylsulfonyl-methyl-propionamide; N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfanylmethyl]-3-benzylsulfanyl-propionamide; N-cyanomethyl-3-(2-trifluoromethyl-benzylsulfanyl)-2-(2-trifluoro-methyl-benzylsulfanylmethyl)-propionamide; N-cyanomethyl-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide; N-cyanomethyl-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide; N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfanylmethyl]-propionamide; 3-benzylsulfanyl-2-benzylsulfanylmethyl-N-cyanomethyl-propionamide; N-cyanomethyl-2-[2-1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide; N-cyanomethyl-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide; 4-benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N-cyanomethyl-butyramide; N-cyanomethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfonyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-propionamide; N-cyanomethyl-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide; N-cyanomethyl-3-(2-methyl-propane-1-sulfonyl)-2-(2-methyl-propane-1-sulfonylmethyl)-propionamide; N-cyanomethyl-3-(2-methyl-thiazol-4-ylmethylsulfonyl)-2-benzyl-sulfonylmethyl-propionamide; 3-biphenyl-3-yl-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzyl-sulfonylmethyl]-propionamide; (3′-{2-(cyanomethyl-carbamoyl)-3-[2-(1,1-difluoro-methoxy)-benzyl-sulfonyl]-propyl}-biphenyl-4-yl)-carbamic acid ethyl ester; N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-(4′-methylsulfonylamino-biphenyl-3-yl)-propionamide; 3-(3-bromo-phenyl)-N-cyanomethyl-2-[2-(1,1-difluoro-methoxy)-phenyl-methylsulfonylmethyl]-propionamide; N-cyanomethyl-2-((E)-3-phenyl-allyl)-3-benzylsulfonyl-propionamide; and N-cyanomethyl-3-benzylsulfonyl-2-(3-phenyl-propyl)-propionamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 10. The compound of claim 7 of Formula I(b):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 11. The compound of claim 10 in which R⁵ is 1H-benzoimidazol-2-yl, benzooxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, benzothiazol-2-yl, 5-phenyl-[1,3,4]oxadiazol-2-yl, 4-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl, 5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl, 5-pyridazin-3-yl-[1,3,4]oxadiazol-2-yl, pyrimidin-2-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]oxadiazol-5-yl, 5-methoxymethyl-[1,3,4]oxadiazol-2-yl, 5-ethyl-[1,3,4]oxadiazol-2-yl, 1,3,4]thiadiazol-2-yl, benzyloxycarbonyl, benzyloxydicarbonyl, phenyldicarbonyl, 5-methyl-[1,3,4]thiadiazol-2-yl, 5-trifluoromethyl-[1,3,4]oxadiazol-2-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, 5-phenyl-[1,2,4]oxadiazol-3-yl, 5-thiophen-3-yl-[1,2,4]oxadiazol-3-yl, 5-trifluoromethyl-[1,2,4]oxadiazol-3-yl, 3-methyl-[1,2,4]oxadiazol-5-yl or 3-pyrazin-2-yl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 12. The compound of claim 11 selected from the group consisting of N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-(2-trifluoromethyl-benzylsulfonyl)-2-(2-trifluoromethyl-benzylsulfonylmethyl)-propionamide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-(2-methoxy-benzenesulfonyl)-2-[2-(2-methoxy-benzenesulfonyl)-ethyl]-butyramide; 4-Benzenesulfonyl-2-(2-benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-butyramide; (R)—N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-2-cyclohexylmethyl-3-benzylsulfonyl-propionaminde; N—[(S)-1-(1-benzothiazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-cyclohexyl-2-cyclohexylmethyl-propionamide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-isobutylsulfanyl-2-isobutylsulfanylmethyl-propionamide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyramide; N—[(S)-1-(1-benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-pentyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-{(S)-1-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-methanoyl]-propyl}-butyramide; N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-2-[2-(1,1-difluoro-methoxy)-benzylsulfonylmethyl]-3-benzylsulfonyl-propionamide; 4-Morpholin-4-yl-4-oxo-N-[1-(2-oxo-2-phenyl-acetyl)-pentyl]-2-benzylsulfonylmethyl-butyramide; N-(1,1-Dimethyl-2-oxazolo[4,5-b]pyridin-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide; N-[1-(5-Ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide; N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide; N-[1-(5-Methoxymethyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-piperidin-1-yl-butyramide; 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide; N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-butyramide; N-[1-(Oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonyl-methyl-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 4-Oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 4-Oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-4-pyrrolidin-1-yl-butyramide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N-[1-(5-pyridin-3-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide; 2-Cyclohexylmethyl-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide; 2-Cyclohexylmethyl-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide; N-(2-Benzooxazol-2-yl-1-methoxymethyl-2-oxo-ethyl)-2-(2-difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyramide; 2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-butyramide; 2-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; 2-(2-Difluoromethoxy-benzylsulfonylmethyl)-N-[1-(5-ethyl-[1,3,4]oxadiazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-butyramide; N-[1-(Benzooxazole-2-carbonyl)-propyl]-2-(2-difluoromethoxy-benzyl-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, 1-(benzooxazole-2-carbonyl)-propyl]-amide; (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, (S)-1-(5-phenyl-[1,2,4]oxadiazole-3-carbonyl)-propyl]-amide; 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-N—[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide; (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-cabonyl)-propyl]-butyramide; 4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide; N-(1,1-Dimethyl-2-oxazol-2-yl-2-oxo-ethyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-4-Isopropyl-N-1-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-2-benzylsulfonylmethyl-succinamide; 2-(2-Difluoromethoxy-benzylsulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide; 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide; 2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-butyramide; N-[1-(Benzooxazole-2-carbonyl)-butyl]-2-benzylsulfonyl-3-(tetrahydro-pyran-4-yloxymethyl)-propionamide; N-[1-(Benzooxazole-2-carbonyl)-butyl]-3-ethanesulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide; N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-cyclopropylmethylsulfonyl-methyl-4-morpholin-4-yl-4-oxo-butyramide; 2-Cyclopropylmethylsulfonylmethyl-N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide; N-{(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid {(S)-1-[(R)-hydroxy-(3-phenyl-1,2,4-oxadiazol-5-yl)-methyl]-propyl}-amide; 2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide; 2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N—[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide; 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, (S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl}-amide; N-[(1S)-1-(Benzooxazol-2-yl-hydroxy-methyl)-3-phenyl-propyl]-2-cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyramide; (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid, 1-(benzoxazole-2-carbonyl)-propyl]-amide; (R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid, 1-(benzoxazole-2-carbonyl)-propyl]-amide; and 4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-cyclopropyl]-4-oxo-2-benzylsulfonyl methyl-butyramide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof, and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 13. The compound of claim 7 of Formula I(c):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 14. The compound of claim 13 in which R⁵ is phenyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 15. The compound of claim 14 selected from the group consisting of N—[(S)-1-((E)-2-benzenesulfonyl-vinyl)-pentyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide and N-(3-benzenesulfonyl-1-phenethyl-allyl)-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 16. The compound of claim 7 of Formula I(d):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 17. The compound of claim 16 in which R⁵ is phenyl and R⁶ is hydrogen; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 18. The compound of claim 17 namely N-(3-benzenesulfonylamino-2-oxo-propyl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 19. The compound of claim 7 of Formula I(e):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 20. The compound of claim 19 in which R⁵ and R⁶ is methyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 21. The compound of claim 20 in which one X⁷ is morpholine-4-carbonyl and the other is benzylsulfonyl, R¹ is hydrogen and R² is ethyl, namely (S)-2,2-difluoro-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-3-oxo-hexanoic acid dimethylamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 22. The compound of claim 7 of Formula I(f):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 23. The compound of claim 22 in which R⁵ is methyl, benzyl, phenethyl, cyclohexyl, methoxyethyl, dimethylaminoethyl, tetrahydro-pyran-4-yl, 1-methylsulfonyl-piperidin-4-yl, 4-methyl-piperazin-1-yl, morpholin-4-ylethyl, pyridin-2-yl, pyridin-2-ylmethyl or oxazol-2-ylmethyl; R⁶ is hydrogen or methyl; or R⁵ and R⁶ together with the nitrogen atom to which both R⁵ and R⁶ are attached form morpholine-4-yl, pyrrolidin-1-yl, 4-dimethylamino-piperazin-1-yl, 4-hydroxy-piperazin-1-yl, 4-pyridin-2-yl-piperazin-1-yl, 4-benzoyl-piperazin-1-yl or 3-oxo-piperazin-1-yl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 24. The compound of claim 23 selected from the group consisting of N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide and N—[(S)-1-(1-Benzylcarbamoyl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 25. The compound of claim 7 of Formula I(g):

and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 26. The compound of claim 25 in which X³ is 1-benzoyl-4-oxo-pyrrolidin-3-yl, 4-oxo-pyrrolidin-3-yl-1-carboxylic acid tert-butyl ester, 2-methyl-4-oxo-tetrahydro-furan-3-yl, 2-ethyl-4-oxo-tetrahydro-furan-3-yl, 4-oxo-tetrahydro-furan-3-yl, 2-acetoxy-4-oxo-azetidin-3-yl, 1-isopropyl-3-oxo-azepan-4-yl, 3-oxo-azepan-4-yl-1-carboxylic acid benzyl ester, 3-oxo-azepan-4-yl-1-carboxylic acid tert-butyl ester, 1-benzoyl-3-oxo-azepan-4-yl, 1-isobutyryl-3-oxo-azepan-4-yl, 3-oxo-1-(propane-2-sulfonyl)-azepan-4-yl, 1-benzenesulfonyl-3-oxo-azepan-4-yl, 1-benzenesulfonyl-3-oxo-piperidin-4-yl, 1-benzenesulfonyl-4-oxo-pyrrolidin-3-yl, 1-benzoyl-3-oxo-piperidin-4-yl or 3-oxo-tetrahydro-pyran-4-yl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 27. The compound of claim 23 selected from the group consisting of 3-Hydroxy-4-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-azepane-1-carboxylic acid tert-butyl ester; 4-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-hydroxy-azepane-1-carboxylic acid tert-butyl ester; 3-Hydroxy-4-[2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-azepane-1-carboxylic acid tert-butyl ester; 4-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic acid tert-butyl ester; 4-(2-Cyclopropylmethylsulfonylmethyl-4-morpholin-4-yl-4-oxo-butyrylamino)-3-oxo-azepane-1-carboxylic acid tert-butyl ester; 4-[2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyrylamino]-3-oxo-azepane-1-carboxylic acid tert-butyl ester; N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide; N-(1-Benzenesulfonyl-3-oxo-azepan-4-yl)-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide; 3-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester; 4-(4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-3-oxo-azepane-1-carboxylic acid benzyl ester; and acetic acid (2S,3S)-3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butanoylamino)-4-oxo-azetidin-2-yl ester; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 28. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.
 29. A method for treating a disease in an animal in which inhibition of Cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of claim 1 or a N-oxide derivative or individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt or solvate of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
 30. The use of a compound of claim 1 in the manufacture of a medicament for treating a disease in an animal in which Cathepsin S activity contributes to the pathology and/or symptomology of the disease.
 31. A process for preparing a compound of Formula I:

in which: X¹ is —C(R¹)(R²)X² or —X³; X² is cyano, —CHO, —C(R⁷)(R⁸)R⁵, —C(R⁷)(R⁸)CF₃, —C(R⁷)(R⁸)CF₂CF₂R⁹—CH═CHS(O)₂R⁵, —C(R⁸)CF₂C(O)NR⁵R⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)NR⁵R⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)OR⁵, —C(R⁷)(R⁸)CH₂OR⁵, —C(R⁷)(R⁸)CH₂N(R⁶)SO₂R⁵, —C(R⁷)(R⁸)C(R⁷)(R⁸)N(R⁶)(CH₂)₂OR⁶, —C(R⁷)(R⁸)C(R⁷)(R⁸)N(R⁶)(CH₂)₂NR⁶ or —C(R⁷)(R⁸)C(R⁷)(R⁸)R⁵; wherein R⁵ is (C₁₋₄)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₄₋₁₀)aryl(C₀₋₆)alkyl, (C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl or hetero(C₄₋₁₀)cycloalkyl(C₀₋₆)alkyl; R⁶ is hydrogen or (C₁₋₆)alkyl; R⁷ is hydrogen or (C₁₋₄)alkyl and R⁸ is hydroxy or R⁷ and R⁸ together form oxo; R⁹ is hydrogen, halo, (C₁₋₄)alkyl, (C₅₋₁₀)aryl(C₀₋₆)alkyl or hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl; X³ represents a group of Formula (a):

in which n is 1 or 2, z is 0 or 1, X⁵ is selected from NR¹⁰, S or O, wherein R¹⁰ is hydrogen or (C₁₋₆)alkyl, and X⁶ is O, S or NR¹¹, wherein R¹¹ is selected from hydrogen, (C₁₋₆)alkyl, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵ and —X⁴S(O)₂NR¹²R¹⁵, in which X⁴ is a bond or (C₁₋₆)alkylene; R¹² at each occurrence independently is hydrogen or (C₁₋₆)alkyl; R¹³ is hydrogen, (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, R¹⁴ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl and R¹⁵ is (C₃₋₁₀)cycloalkyl(C₀₋₆)alkyl, hetero(C₃₋₁₀)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₀)aryl(C₀₋₆)alkyl, hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₆)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₆)alkyl; wherein within X¹ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R²⁰ selected from —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹²; and wherein X¹ and R²⁰ may be substituted further with 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴ wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; R¹ and R² are both fluoro; or R¹ is hydrogen or (C₁₋₆)alkyl and R² is selected from the group consisting of hydrogen, (C₁₋₆)alkyl, cyano, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴ SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴, —X⁴S(O)₂R¹⁴, —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; or R¹ and R² taken together with the carbon atom to which both R¹ and R² are attached form (C₃₋₈)cycloalkylene or hetero(C₃₋₈)cycloalkylene; wherein R², said cycloalkylene and said heterocycloalkylene may be substituted further with 1 to 3 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above; R³ and R⁴ are independently —C(R¹⁶)(R¹⁷)X⁷, wherein R¹⁶ and R¹⁷ are hydrogen, (C₁₋₆)alkyl or fluoro, or R¹⁶ is hydrogen and R¹⁷ is hydroxy and X⁷ is selected from —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴, —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹⁵R¹², —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(NR¹²)NR¹⁵R¹², wherein X⁴, R¹², R¹³, R¹⁴ and R¹⁵ are as defined above; wherein within one of R³ or R⁴ any cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted with 1 radical R²¹ selected from —R¹⁵, —X⁴OR¹⁵, —X⁴SR¹⁵, —X⁴S(O)R¹⁵, —X⁴S(O)₂R¹⁵, —X⁴C(O)R¹⁵, —X⁴C(O)OR¹⁵, —X⁴OC(O)R¹⁵, —X⁴NR¹⁵R¹², —X⁴NR¹²C(O)R¹⁵, —X⁴NR¹²C(O)OR¹⁵, —X⁴C(O)NR¹²R¹⁵, —X⁴S(O)₂NR¹⁵R¹², —X⁴NR¹²S(O)₂R¹⁵, —X⁴NR¹²C(O)NR¹⁵R¹² and —X⁴NR¹²C(N¹²)NR¹⁵R¹², wherein X⁴, R¹² and R¹⁵ are as defined above; and wherein each of R³, R⁴ and R²¹ may be substituted further with 1 to 5 radicals independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², —X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above; provided that only one bicyclic ring structure is present within each of R³ or R⁴; and provided that when X² is cyano and X⁷ within one of R³ or R⁴ is —X⁴C(O)R¹³ or —X⁴C(O)R¹⁵, wherein X⁴ is a bond, then X⁷ within the other of R³ or R⁴ is limited to —X⁴SR¹⁵, —X⁴S(O)R¹⁵ and —X⁴S(O)₂R¹⁵, wherein R¹⁵ is (C₆₋₁₀)aryl(C₁₋₆)alkyl substituted with 1 to 5 radicals or hetero(C₅₋₁₀)aryl(C₀₋₆)alkyl optionally substituted with 1 to 5 radicals, wherein said radicals are independently selected from (C₁₋₆)alkyl, cyano, halo, halo-substituted(C₁₋₄)alkyl, nitro, —X⁴NR¹²R¹², —X⁴NR¹²C(O)R¹², —X⁴NR¹²C(O)OR¹², —X⁴NR¹²C(O)NR¹²R¹², X⁴NR¹²C(NR¹²)NR¹²R¹², —X⁴OR¹³, —X⁴SR¹³, —X⁴C(O)OR¹², —X⁴C(O)R¹³, —X⁴OC(O)R¹³, —X⁴C(O)NR¹²R¹², —X⁴S(O)₂NR¹²R¹², —X⁴NR¹²S(O)₂R¹³, —X⁴P(O)(OR¹²)OR¹², —X⁴OP(O)(OR¹²)OR¹², —X⁴S(O)R¹⁴ and —X⁴S(O)₂R¹⁴, wherein X⁴, R¹², R¹³ and R¹⁴ are as defined above, provided that the radical is not selected from only halo when R¹⁵ is (C₆₋₁₀)aryl(C₁₋₆)alkyl; and provided that when X² is cyano then X⁷ within R³ and R⁴ is not —X⁴C(O)NR¹²R¹², —X⁴C(O)NR¹⁵R¹² or —X⁴C(O)NR¹⁸R¹⁹, wherein X⁴ is a bond and R¹⁸ and R¹⁹ together with the nitrogen atom to which they are attached form hetero(C₃₋₁₀)cycloalkyl or hetero(C₅₋₁₀)aryl; and the corresponding N-oxides, and their prodrugs, and their protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds of formula I and their N-oxides and their prodrugs, and their protected derivatives, individual isomers and mixtures of isomers thereof; which process comprises: (A) reacting a compound of Formula 2:

with a compound of the formula NH₂CR¹R²X², in which X², R¹, R², R³ and R⁴ are as defined in the Summary of the Invention for Formula I; or (B) reacting a compound of Formula 2 with a compound of the formula NH₂X³, in which X³, R³ and R⁴ are as defined in the Summary of the Invention for Formula I; or (C) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; (D) optionally converting a salt form of a compound of Formula I to non-salt form; (E) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; (F) optionally converting an N-oxide form of a compound of Formula I its unoxidized form; (G) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers; (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and (I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form. 